Europen Archives of :Medical Research 2018-Suppl by LookUs Scientific

ISSN 2651-3137 • EISSN 2651-3153

European Archives of Medical Research Formerly Journal of the Okmeydanı Medical Journal

Volume: 34 • Supplement: 1 • December 2018 Technological Innovations’ Effects on Medicine Highlights • Artificial Intelligence in Medicine

Süleyman Sami Çakır, Alper Ötünçtemur; İstanbul, Turkey

• Innovations in Orthopedic Surgery: How to Change Good to Perfect?

Haluk Çabuk; İstanbul, Turkey

• Technological Advancements in Nuclear Medicine and Molecular Imaging

Levent Güner, Kemal Ünal, Erkan Vardareli; İstanbul, Turkey

• Impact of Technological Advancements in Otolaryngology

Berk Gürpınar, Ayça Başkadem Yılmazer, Yavuz Uyar; İstanbul, Turkey

• Technological Innovations in Intensive Care Unit

Esra Akdaş Tekin, Ömür Gökkaya, Seray Türkmen, Şule Vatansever, Namigar Turgut; İstanbul, Turkey

• Use of the Robots, Virtual Reality and Other Technological Devices in Rehabilitation

Sevgi Atar, Berrin Hüner, Ömer Kuru; İstanbul, Turkey

• Technology Innovations in Urology

Recep Burak Değirmentepe, Emre Can Polat, Alper Ötünçtemur; İstanbul, Turkey

Official Journal of Health Sciences University Okmeydanı Training and Research Hospital eurarchmedres.org

Formerly Journal of the Okmeydanı Medical Journal Editor in Chief Tamer Özülker

Department of Nuclear Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0001-9521-683X

Associate Editors Müjdat Adaş

Section Editors of This Issue

Department of Orthopedics and Traumatology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-3637-8876

Tamer Özülker

Namigar Turgut

Alper Ötünçtemur

Department of Anesthesiology and Reanimation, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-0252-3377

Yavuz Uyar

Department of Anesthesiology and Reanimation, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-0252-3377

Biostatistical Consultants Ebru Osmanoğlu Akyol

Varyans Statistics Consultancy, İstanbul, Turkey

Deniz Özel Erkan

Akdeniz University School of Medicine, Antalya, Turkey

Editorial Staff Kübra Sunkar

Department of Nuclear Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey Department of Urology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Hakan Önder

Department of Radiology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Burak Erden

Department of Eye Diseases, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-0650-4552

Funda Şimşek

Department of Infectious Diseases and Departmental Microbiology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0002-7387-5057

Hakan Önder

Department of Radiology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Hasan Dursun

Editors Alper Ötünçtemur

Department of Urology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0002-0553-3012

Arzu Akan

Department of General Surgery, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Asım Kalkan

Department of Emergency Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Berrin Hüner

Department of Physical Medicine and Rehabilitation, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-3584-8880

Department of Pediatrics, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0002-8817-494X

Mehmet Küçük

Özge Kandemir Gürsel

Department of Radiation Oncology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0002-6960-4115

Özgür Emek Kocatürk Göncü

Department of Dermatology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-2801-0959

Seçil Arıca

Department of Family Practice, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Serap Üçler

Department of Neurology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Şener Cihan

Department of Internal Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Department of Medical Oncology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0002-3594-3661

Mine Adaş

Tamer Altay

Department of Internal Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0003-3008-6581

Nihan Kayalar

Department of Neurosurgery, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Tolgar Lütfi Kumral

Department of Cardiovascular Surgery, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Department of Otorhinolaryngology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey ORCID ID: 0000-0001-8760-7216

Özben Yalçın

Veli Mihmanlı

Department of Pathology, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Department of Gynecology and Obstetrics, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey

Sağlık Bilimleri Üniversitesi Okmeydanı Eğitim ve Araştırma Hastanesi adına sahibi ve Sorumlu Yazı İşleri Müdürü / Owner on behalf and Responsible Manager of Health Sciences University Okmeydanı Training and Research Hospital: Hakan Gürbüz • Yayın türü / Publication Type: Yerel süreli / Local periodical • Basım yeri / Printed at: Matsis Matbaa Hizmetleri San. ve Tic. Ltd. Şti. Tevfikbey Mah. Dr. Ali Demir Cad. No: 51 Sefaköy, İstanbul, Turkey (+90 212 624 21 11) • Basım tarihi / Printing Date: Ekim 2018 / October 2018 • Sağlık Bilimleri Üniversitesi Okmeydanı Eğitim ve Araştırma Hastanesi tarafından yayınlanmaktadır / Published by Health Sciences University Okmeydanı Training and Research Hospital, Kaptan Paşa Mahallesi, Darülaceze Cad. No:25, 34384 Okmeydanı/Şişli/İstanbul (+90 212 314 55 55)

Publisher İbrahim KARA

Editorial Development Gizem KAYAN

Publication Director Ali ŞAHİN

Publication Coordinators Betül ÇİMEN Özlem ÇAKMAK Okan AYDOĞAN İrem DELİÇAY Arzu YILDIRIM

Finance and Administration Zeynep YAKIŞIRER Deputy Publication Director Gökhan ÇİMEN

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Project Assistants Ecenur ASLIM Doğan ORUÇ Sinem KOZ Graphics Department Ünal ÖZER Deniz DURAN Beyzanur KARABULUT

Contact Address: Büyükdere Cad. 105/9 34394 Mecidiyeköy, Şişli, İstanbul Phone: +90 212 217 17 00 Fax: +90 212 217 22 92 E-mail: info@avesyayincilik.com

Formerly Journal of the Okmeydanı Medical Journal

AIMS AND SCOPE European Archives of Medical Research (Eur Arch Med Res) is the scientific, peer-reviewed, open access publication of Health Sciences University, Okmeydanı Training and Research Hospital. The journal is a quarterly publication, published on January, April, July, and October. The publication language of the journal is English. European Archives of Medical Research aims to contribute to the international literature by publishing original clinical and experimental research articles, case reports, review articles, and letters to the editor on all fields of medicine. The target audience of the journal includes researchers, general practitioners and specialists from all fields of medicine. The editorial and publication processes of the journal are shaped in accordance with the guidelines of the International Committee of Medical Journal Editors (ICMJE), World Association of Medical Editors (WAME), Council of Science Editors (CSE), Committee on Publication Ethics (COPE), European Association of Science Editors (EASE), and National Information Standards Organization (NISO). The journal is in conformity with the Principles of Transparency and Best Practice in Scholarly Publishing (doaj.org/bestpractice). European Archives of Medical Research is currently indexed in TUBITAK ULAKBIM TR Index and EBSCO Academic Search Complate. Processing and publication are free of charge with the journal. No fees are requested from the authors at any point throughout the evaluation and publication process. All manuscripts must be submitted via the online submission system, which is available at eurarchmedres.org. The journal guidelines, technical information, and the required forms are available on the journal’s web page. All expenses of the journal are covered by the Health Sciences University, Okmeydanı Training and Research Hospital. Potential advertisers should contact the Editorial Office. Advertisement images are published only upon the Editor-in-Chief’s approval. Statements or opinions expressed in the manuscripts published in the journal reflect the views of the author(s) and not the opinions of the Health Sciences University, Okmeydanı Training and Research Hospital, editors, editorial board, and/or publisher; the editors, editorial board, and publisher disclaim any responsibility or liability for such materials. All published content is available online, free of charge at eurarchmedres.org. Printed copies of the journal are distributed to the members of the Health Sciences University, Okmeydanı Training and Research Hospital, free of charge. European Archives of Medical Research is an open access publication and the journal’s publication model is based on Budapest Open Access Initiative (BOAI) declaration. Journal’s archive is available online, free of charge at eurarchmedres.org. European Archives of Medical Research’s content is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Editor in Chief: Tamer Özülker Address: Department of Nuclear Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey Phone: +90 212 314 63 24 E-mail: tozulker@gmail.com Publisher: AVES Address: Büyükdere Cad., 105/9 34394 Mecidiyeköy, Şişli, İstanbul, Turkey Phone: +90 212 217 17 00 Fax: +90 212 217 22 92 E-mail: info@avesyayincilik.com Web page: avesyayincilik.com

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Formerly Journal of the Okmeydanı Medical Journal

INSTRUCTIONS TO AUTHORS European Archives of Medical Research (Eur Arch Med Res) is the scientific, peerreviewed, open access publication of Health Sciences University, Okmeydanı Training and Research Hospital. The journal is a quarterly publication, published on January, April, July and October. The publication language of the journal is English. The aim of the European Archives of Medical Research is to publish original research papers of the highest scientific and clinical value in all medical fields. Eur Arch Med Res also includes reviews, rare case reports, and letters to the editor that are related to recently published articles. The editorial and publication processes of the journal are shaped in accordance with the guidelines of the International Council of Medical Journal Editors (ICMJE), the World Association of Medical Editors (WAME), the Council of Science Editors (CSE), the Committee on Publication Ethics (COPE), the European Association of Science Editors (EASE), and National Information Standards Organization (NISO). The journal conforms to the Principles of Transparency and Best Practice in Scholarly Publishing (doaj.org/bestpractice). Originality, high scientific quality, and citation potential are the most important criteria for a manuscript to be accepted for publication. Manuscripts submitted for evaluation should not have been previously presented or already published in an electronic or printed medium. The journal should be informed of manuscripts that have been submitted to another journal for evaluation and rejected for publication. The submission of previous reviewer reports will expedite the evaluation process. Manuscripts that have been presented in a meeting should be submitted with detailed information on the organization, including the name, date, and location of the organization. Manuscripts submitted to European Archives of Medical Research will go through a double-blind peer-review process. Each submission will be reviewed by at least two external, independent peer reviewers who are experts in their fields in order to ensure an unbiased evaluation process. The editorial board will invite an external and independent editor to manage the evaluation processes of manuscripts submitted by editors or by the editorial board members of the journal. The Editor in Chief is the final authority in the decision-making process for all submissions. An approval of research protocols by the Ethics Committee in accordance with international agreements (World Medical Association Declaration of Helsinki “Ethical Principles for Medical Research Involving Human Subjects,” amended in October 2013, www.wma.net) is required for experimental, clinical, and drug studies and for some case reports. If required, ethics committee reports or an equivalent official document will be requested from the authors. For manuscripts concerning experimental research on humans, a statement should be included that shows that written informed consent of patients and volunteers was obtained following a detailed explanation of the procedures that they may undergo. For studies carried out on animals, the measures taken to prevent pain and suffering of the animals should be stated clearly. Information on patient consent, the name of the ethics committee, and the ethics committee approval number should also be stated in the Methods section of the manuscript. It is the authors’ responsibility to carefully protect the patients’ anonymity. For photographs that may reveal the identity of the patients, signed releases of the patient or of their legal representative should be enclosed. All submissions are screened by a similarity detection software (iThenticate by CrossCheck). In the event of alleged or suspected research misconduct, e.g., plagiarism, citation manipulation, and data falsification/fabrication, the Editorial Board will follow and act in accordance with COPE guidelines. Each individual listed as an author should fulfill the authorship criteria recommended by the International Committee of Medical Journal Editors (ICMJE - www.icmje.org). The ICMJE recommends that authorship be based on the following 4 criteria: 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND

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2. Drafting the work or revising it critically for important intellectual content; AND 3. Final approval of the version to be published; AND 4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. In addition to being accountable for the parts of the work he/she has done, an author should be able to identify which co-authors are responsible for specific other parts of the work. In addition, authors should have confidence in the integrity of the contributions of their co-authors. All those designated as authors should meet all four criteria for authorship, and all who meet the four criteria should be identified as authors. Those who do not meet all four criteria should be acknowledged in the title page of the manuscript. European Archives of Medical Research requires corresponding authors to submit a signed and scanned version of the authorship contribution form (available for download through eurarchmedres.org) during the initial submission process in order to act appropriately on authorship rights and to prevent ghost or honorary authorship. If the editorial board suspects a case of “gift authorship,” the submission will be rejected without further review. As part of the submission of the manuscript, the corresponding author should also send a short statement declaring that he/she accepts to undertake all the responsibility for authorship during the submission and review stages of the manuscript. European Archives of Medical Research requires and encourages the authors and the individuals involved in the evaluation process of submitted manuscripts to disclose any existing or potential conflicts of interests, including financial, consultant, and institutional, that might lead to potential bias or a conflict of interest. Any financial grants or other support received for a submitted study from individuals or institutions should be disclosed to the Editorial Board. To disclose a potential conflict of interest, the ICMJE Potential Conflict of Interest Disclosure Form should be filled in and submitted by all contributing authors. Cases of a potential conflict of interest of the editors, authors, or reviewers are resolved by the journal’s Editorial Board within the scope of COPE and ICMJE guidelines. The Editorial Board of the journal handles all appeal and complaint cases within the scope of COPE guidelines. In such cases, authors should get in direct contact with the editorial office regarding their appeals and complaints. When needed, an ombudsperson may be assigned to resolve cases that cannot be resolved internally. The Editor in Chief is the final authority in the decision-making process for all appeals and complaints. European Archives of Medical Research requires each submission to be accompanied by a Copyright License Agreement (available for download eurarchmedres.org). When using previously published content, including figures, tables, or any other material in both print and electronic formats, authors must obtain permission from the copyright holder. Legal, financial and criminal liabilities in this regard belong to the author(s). By signing the Copyright License Agreement, authors agree that the article, if accepted for publication by the European Archives of Medical Research, will be licensed under a Creative Commons Attribution-Non Commercial 4.0 International License (CC-BY-NC). Statements or opinions expressed in the manuscripts published in European Archives of Medical Research reflect the views of the author(s) and not the opinions of the editors, the editorial board, or the publisher; the editors, the editorial board, and the publisher disclaim any responsibility or liability for such materials. The final responsibility in regard to the published content rests with the authors. Statements or opinions expressed in the manuscripts published in European Archives of Medical Research reflect the views of the author(s) and not the opinions of the editors, the editorial board, or the publisher; the editors, the editorial board, and the publisher disclaim any responsibility or liability for such materials. The final responsibility in regard to the published content rests with the authors.

Formerly Journal of the Okmeydanı Medical Journal

MANUSCRIPT PREPARATION The manuscripts should be prepared in accordance with ICMJE-Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals (updated in December 2017 - http://www.icmje.org/icmje-recommendations.pdf). Authors are required to prepare manuscripts in accordance with the CONSORT guidelines for randomized research studies, STROBE guidelines for observational original research studies, STARD guidelines for studies on diagnostic accuracy, PRISMA guidelines for systematic reviews and meta-analysis, ARRIVE guidelines for experimental animal studies, and TREND guidelines for non-randomized public behavior. Manuscripts can only be submitted through the journal’s online manuscript submission and evaluation system, available at eurarchmedres.org. Manuscripts submitted via any other medium will not be evaluated. Manuscripts submitted to the journal will first go through a technical evaluation process where the editorial office staff will ensure that the manuscript has been prepared and submitted in accordance with the journal’s guidelines. Submissions that do not conform to the journal’s guidelines will be returned to the submitting author with technical correction requests. Authors are required to submit the following: • Copyright Licence Agreement, • Author Contributions Form, and • ICMJE Potential Conflict of Interest Disclosure Form (should be filled in by all contributing authors) during the initial submission. These forms are available for download at eurarchmedres.org. Preparation of the Manuscript All manuscripts should be submitted in 12 point Times New Roman type with 2 line spacing. Title page: A separate title page should be submitted with all submissions and this page should include: • The full title of the manuscript as well as a short title (running head) of no more than 50 characters,

structured with Introduction, Methods, Results, Discussion, and Conclusion subheadings. Please check Table 1 for the limitations for Original Articles. Statistical analysis to support conclusions is usually necessary. Statistical analyses must be conducted in accordance with international statistical reporting standards (Altman DG, Gore SM, Gardner MJ, Pocock SJ. Statistical guidelines for contributors to medical journals. Br Med J 1983: 7; 1489-93). Information on statistical analyses should be provided with a separate subheading under the Materials and Methods section and the statistical software that was used during the process must be specified. Units should be prepared in accordance with the International System of Units (SI). Editorial Comments: Editorial comments aim to provide a brief critical commentary by reviewers with expertise or with high reputation in the topic of the research article published in the journal. Authors are selected and invited by the journal to provide such comments. Abstract, Keywords, and Tables, Figures, Images, and other media are not included. Review Articles: Reviews prepared by authors who have extensive knowledge on a particular field and whose scientific background has been translated into a high volume of publications with a high citation potential are welcomed. These authors may even be invited by the journal. Reviews should describe, discuss, and evaluate the current level of knowledge of a topic in clinical practice and should guide future studies. The main text should contain Introduction, Clinical and Research Consequences, and Conclusion sections. Please check Table 1 for the limitations for Review Articles. Case Reports: There is limited space for case reports in the journal and reports on rare cases or conditions that constitute challenges in diagnosis and treatment, those offering new therapies or revealing knowledge not included in the literature, and interesting and educative case reports are accepted for publication. The text should include Introduction, Case Presentation, Discussion, and Conclusion subheadings. Please check Table 1 for the limitations for Case Reports. Letters to the Editor: This type of manuscript discusses important parts, overlooked aspects, or lacking parts of a previously published article. Articles on subjects within the scope of the journal that might attract the readers’ attention, particularly educative cases, may also be submitted in the form of a “Letter to the Editor.” Readers can also present their comments on the published manuscripts in the form of a “Letter to the Editor.” Abstract, Keywords, and Tables, Figures, Images, and other media should not be included. The text should be unstructured. The manuscript that is being commented on must be properly cited within this manuscript.

• Name(s), affiliations, highest academic degree(s), e-mail addresses, and ORCID IDs of the author(s),

Tables

• Grant information and detailed information on the other sources of support,

Tables should be included in the main document, presented after the reference list, and they should be numbered consecutively in the order they are referred to

• Name, address, telephone (including the mobile phone number) and fax numbers, and email address of the corresponding author, • Acknowledgment of the individuals who contributed to the preparation of the manuscript but who do not fulfill the authorship criteria. Abstract: An abstract should be submitted with all submissions except for Letters to the Editor. The abstract of Original Articles should be structured with subheadings (Objective, Methods, Results, and Conclusion). Please check Table 1 below for word count specifications. Keywords: Each submission must be accompanied by a minimum of three to a maximum of six keywords for subject indexing at the end of the abstract. The keywords should be listed in full without abbreviations. The keywords should be selected from the National Library of Medicine, Medical Subject Headings database (https://www. nlm.nih.gov/mesh/MBrowser.html). Manuscript Types Original Articles: This is the most important type of article since it provides new information based on original research. The main text of original articles should be

Table 1. Limitations for each manuscript type Type of manuscript

Word limit

Abstract word limit

Reference limit

Table limit

Figure limit

Original Article

3500

250 (Structured)

7 or total of 15 images

Review Article

5000

250

10 or total of 20 images

Case Report

1000

200

No tables

10 or total of 20 images

Letter to the Editor

500

No abstract

No tables

No media

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Formerly Journal of the Okmeydanı Medical Journal

within the main text. A descriptive title must be placed above the tables. Abbreviations used in the tables should be defined below the tables by footnotes (even if they are defined within the main text). Tables should be created using the “insert table” command of the word processing software and they should be arranged clearly to provide easy reading. Data presented in the tables should not be a repetition of the data presented within the main text but should be supporting the main text.

Editor(s) as Author: Huizing EH, de Groot JAM, editors. Functional reconstructive nasal surgery. Stuttgart-New York: Thieme;2003.

Figures and Figure Legends

Scientific or Technical Report: Cusick M, Chew EY, Hoogwerf B, Agrón E, Wu L, Lindley A, et al. Early Treatment Diabetic Retinopathy Study Research Group. Risk factors for renal replacement therapy in the Early Treatment Diabetic Retinopathy Study (ETDRS), Early Treatment Diabetic Retinopathy Study Kidney Int: 2004. Report No: 26.

Figures, graphics, and photographs should be submitted as separate files (in TIFF or JPEG format) through the submission system. The files should not be embedded in a Word document or the main document. When there are figure subunits, the subunits should not be merged to form a single image. Each subunit should be submitted separately through the submission system. Images should not be labeled (a, b, c, etc.) to indicate figure subunits. Thick and thin arrows, arrowheads, stars, asterisks, and similar marks can be used on the images to support figure legends. Like the rest of the submission, the figures too should be blind. Any information within the images that may indicate an individual or institution should be blinded. The minimum resolution of each submitted figure should be 300 DPI. To prevent delays in the evaluation process, all submitted figures should be clear in resolution and large in size (minimum dimensions: 100 × 100 mm). Figure legends should be listed at the end of the main document. All acronyms and abbreviations used in the manuscript should be defined at first use, both in the abstract and in the main text. The abbreviation should be provided in parentheses following the definition. When a drug, product, hardware, or software program is mentioned within the main text, product information, including the name of the product, the producer of the product, and city and the country of the company (including the state if in USA), should be provided in parentheses in the following format: “Discovery St PET/CT scanner (General Electric, Milwaukee, WI, USA)” All references, tables, and figures should be referred to within the main text, and they should be numbered consecutively in the order they are referred to within the main text. Limitations, drawbacks, and the shortcomings of original articles should be mentioned in the Discussion section before the conclusion paragraph. References While citing publications, preference should be given to the latest, most up-to-date publications. If an ahead-of-print publication is cited, the DOI number should be provided. Authors are responsible for the accuracy of references. Journal titles should be abbreviated in accordance with the journal abbreviations in Index Medicus/ MEDLINE/PubMed. When there are six or fewer authors, all authors should be listed. If there are seven or more authors, the first six authors should be listed followed by “et al.” In the main text of the manuscript, references should be cited using Arabic numbers in parentheses. The reference styles for different types of publications are presented in the following examples. Journal Article: Stephane A. Management of Congenital Cholesteatoma with Otoendoscopic Surgery: Case Report. Turkiye Klinikleri J Med Sci 2010; 30: 803-7. Book Section: Suh KN, Keystone JS. Malaria and babesiosis. Gorbach SL, Barlett JG, Blacklow NR, editors. Infectious Diseases. Philadelphia: Lippincott Williams; 2004.p.2290-308. Books with a Single Author: Sweetman SC. Martindale the Complete Drug Reference. 34th ed. London: Pharmaceutical Press;2005.

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Conference Proceedings: Bengisson S. Sothemin BG. Enforcement of data protection, privacy and security in medical informatics. In: Lun KC, Degoulet P, Piemme TE, Rienhoff O, editors. MEDINFO 92. Proceedings of the 7th World Congress on Medical Informatics; 1992 Sept 6-10; Geneva, Switzerland. Amsterdam: NorthHolland;1992. pp.1561-5.

Thesis: Yılmaz B. Ankara Üniversitesindeki Öğrencilerin Beslenme Durumları, Fiziksel Aktiviteleri ve Beden Kitle İndeksleri Kan Lipidleri Arasındaki Ilişkiler. H.Ü. Sağlık Bilimleri Enstitüsü, Doktora Tezi. 2007. Manuscripts Accepted for Publication, Not Published Yet: Slots J. The microflora of black stain on human primary teeth. Scand J Dent Res. 1974. Epub Ahead of Print Articles: Cai L, Yeh BM, Westphalen AC, Roberts JP, Wang ZJ. Adult living donor liver imaging. Diagn Interv Radiol 2016 Feb 24. doi: 10.5152/ dir.2016.15323. [Epub ahead of print]. Manuscripts Published in Electronic Format: Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis (serial online) 1995 Jan-Mar (cited 1996 June 5): 1(1): (24 screens). Available from: URL: http:/ www.cdc.gov/ncidodlElD/cid.htm. REVISIONS When submitting a revised version of a paper, the author must submit a detailed “Response to the reviewers” that states point by point how each issue raised by the reviewers has been covered and where it can be found (each reviewer’s comment, followed by the author’s reply and line numbers where the changes have been made) as well as an annotated copy of the main document. Revised manuscripts must be submitted within 30 days from the date of the decision letter. If the revised version of the manuscript is not submitted within the allocated time, the revision option may be canceled. If the submitting author(s) believe that additional time is required, they should request this extension before the initial 30-day period is over. Accepted manuscripts are copy-edited for grammar, punctuation, and format. Once the publication process of a manuscript is completed, it is published online on the journal’s webpage as an ahead-of-print publication before it is included in its scheduled issue. A PDF proof of the accepted manuscript is sent to the corresponding author and their publication approval is requested within 2 days of their receipt of the proof. Editor in Chief: Tamer Özülker Address: Department of Nuclear Medicine, University of Health Sciences Okmeydanı Training and Research Hospital, İstanbul, Turkey Phone: +90 212 314 63 24 E-mail: tozulker@gmail.com Publisher: AVES Address: Büyükdere Cad. 105/9 34394 Mecidiyeköy, Şişli, İstanbul, Turkey Phone: +90 212 217 17 00 Fax: +90 212 217 22 92 E-mail: info@avesyayincilik.com avesyayincilik.com

Formerly Journal of the Okmeydanı Medical Journal

CONTENTS

REVIEWS

Artificial Intelligence in Medicine Süleyman Sami Çakır, Alper Ötünçtemur; İstanbul, Turkey

Artificial Intelligence in Surgery Emin Köse, Nadi Nazım Öztürk, Servet Rüştü Karahan; İstanbul, Turkey

Novel Advances in Oncology Şener Cihan, Serdar Arıcı, Ruhper Çekin; İstanbul, Turkey

S10 Innovations in Genetic Medicine: A Journey in Time Biray Ertürk, Burçin Pehlivanoğlu; İstanbul, Adıyaman, Turkey S13 Technological Innovations in Intensive Care Unit Esra Akdaş Tekin, Ömür Gökkaya, Seray Türkmen, Şule Vatansever, Namigar Turgut; İstanbul, Turkey S19 Innovations in Orthopedic Surgery: How to Change Good to Perfect? Haluk Çabuk; İstanbul, Turkey S22 Technology Innovations in Urology Recep Burak Değirmentepe, Emre Can Polat, Alper Ötünçtemur; İstanbul, Turkey S25 Technological Advancements in Nuclear Medicine and Molecular Imaging Levent Güner, Kemal Ünal, Erkan Vardareli; İstanbul, Turkey S30 The Future of Medical Education Hasan Anıl Atalay, Lütfi Canat, Sait Özbir; İstanbul, Turkey S33 Impact of Technological Advancements in Otolaryngology Berk Gürpınar, Ayça Başkadem Yılmazer, Yavuz Uyar; İstanbul, Turkey S37 Optical Coherence Tomography Angiography: A New Vision Into The Future of Retinal Imaging Burak Erden; İstanbul, Turkey S42 We are Being Introduced to New Developments on the Imaging Field Day by Day Serkan Arıbal, Hakan Önder, Recep Yılmaz Bayraktarlı ; İstanbul, Turkey S46 Fluorescence in Situ Hybridization in Pathology Özben Yalçın, Gamze Kulduk; İstanbul, Turkey S48 Wearable Kidney; Away from Tomorrow but More Real than Dream Mehmet Küçük; İstanbul, Turkey S51 Use of the Robots, Virtual Reality and Other Technological Devices in Rehabilitation Sevgi Atar, Berrin Hüner, Ömer Kuru; İstanbul, Turkey S55 Recent Technological Advances in Radiotherapy Özge Kandemir Gürsel; İstanbul, Turkey S61 Effects of Technological Innovations on Reconstructive Microsurgery; Flap Monitoring Systems After Free Tissue Transfer, Yesterday and Today Özlem Çolak, Özay Özkaya Mutlu, Kadri Özer; İstanbul, Turkey S66 A New Era Has Begun in Neurology Thanks to Gene and Biotechnologies Cihat Örken; İstanbul, Turkey

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Review

Eur Arch Med Res 2018; 34 (Suppl. 1): S1-S3

Artificial Intelligence in Medicine Süleyman Sami Çakır

, Alper Ötünçtemur

Department of Urology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Artificial intelligence (AI) is the science of creating intelligent computer programs. The aim of AI is to help doctors in clinical diagnosis and treatment and to reduce the rate of medical error. The main AI methods used extensively are expert systems (ESs), fuzzy logic, genetic algorithm, and artificial neural networks (ANNs). ESs make inferences with patient data in cause and effect relationships and make recommendations to the doctor. Fuzzy systems aim to produce scientific expressions and approximate results from uncertain data such as those in the field of medicine. ANNs contain neurons that mimic the biological nervous systems. A network is obtained by connecting these neurons in various ways. AI methods continue to evolve even if medical field use has been tested many times. In the present study, a brief evaluation has been made regarding the methods mentioned. Keywords: Artificial intelligence, expert systems, artificial neural networks, fuzzy logic

INTRODUCTION Artificial intelligence (AI) was first used by John McCarthy in 1955. It was defined as “the science and engineering of making intelligent machinery.” At the same time, in 1956, McCarty and colleagues organized a conference on AI in the United States to give rise to a new interdisciplinary field of research. Thus, an intellectual framework was established for all subsequent computer research and efforts (1).

ORCID IDs of the authors: S.S.Ç. 0000-0002-0211-3450; A.Ö. 0000-0002-0553-3012. Cite this article as: Çakır SS, Ötünçtemur A. Artificial Intelligence in Medicine. Eur Arch Med Res 2018; 34 (Suppl. 1): S1-S3. Corresponding Author: Süleyman Sami Çakır E-mail: ssamicakir@hotmail.com Received: 28.08.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.43534 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Artificial intelligence is a computer science that deals with the design of intelligent computer systems. The Intelligent Computer System is a system that is comparable to the intelligence of human behavior. Similar systems of the thinking ability of humans can be established with AI. Its areas of application include robotic, expert systems (ESs), automatic translation programs, meaning analyzers for natural languages (e.g., understanding questions in certain areas and understanding text), natural language sentence production (e.g., abstract poetry writing, story writing, and making computer art/music), audio analyzers (e.g., recognizing certain words in a speech and determining the boundaries between sound units), game programs (e.g., chess and bridge), and theorems proving/ problem solvers (2). Although significant progress has been made in the field of AI in recent years, the efforts of researchers to develop new inventions and programs are ongoing. Expert Systems Expert systems is the most important application area for AI. It is a computer program that aims to replicate the expertize of a specialist on a computer. A well-developed ES has the ability to imitate processes that can be performed by specialists, such as designing, planning, diagnosing, interpreting, summarizing, generalizing, controlling, and making recommendations (2). The data base and inference mechanism are the most important features that distinguish ES from other decision support systems (3). Conventional Programs→Algorithm+Data Base Expert Systems→Inference Mechanism+Data Base Data base is the most central element of the ES. It contains all the information, data, rules, relationships, definition of problems, solutions, and information on how to proceed with the solution.

Çakır and Ötünçtemur. Artificial Intelligence

It is organized by the knowledge engineer as a result of the interviews conducted by experts (4, 5). Expert system’s core includes an inference engine. It provides the analysis of data and rules stored in the data base. It communicates to the user and enables the solution to be achieved by providing reasoning to the system (5). ESs in Medicine Medical ES might be defined as the ES developed to provide structural questions and solutions in the fields of medicine. It is developed in accordance with the recommendations of one or more medical experts. Thus, it is ensured that accurate results are produced by taking into consideration the most appropriate questions. The goal of the medical ES is not to replace the physician but to provide advice to the physician based on the patient’s data. MYCIN is the first and most well-known medical ES developed for the diagnosis and treatment of bacterial infectious diseases at Stanford University (3). It also aimed to reduce the use of antibiotics. It takes patient data, laboratory results, and symptoms and makes diagnosis, prescribes, and performs treatment planning functions. MYCIN is a computer program that informs the patient’s physician about the diagnosis of meningitis and the diseases caused by bacteria in the blood. However, it provides the method of diagnosis and treatment to a specialist in that field only. It is the most well-known of the ES ever developed. Since most of the articles prepared on the ES focus on MYCIN, this ES has played an encouraging role in further studies in this area. The doctor who wants to use MYCIN at Stanford University hospital answers the questions asked by MYCIN. These questions include the patient’s symptoms of discomfort, general information about the patient (e.g., age and gender), and analysis results. In the meantime, when MYCIN asks for information about a test whose results have not yet been obtained, the doctor is able to answer “not known yet” since MYCIN is able to continue to make decisions with incomplete information similar to a specialist. In conclusion, MYCIN reports the diagnosis and recommends the treatment method to the doctor (6-8). The success of MYCIN in the treatment was compared with the experts and it was observed to be more successful. But despite all its features, it has never been used in practice due to ethical issues (for example, who would be responsible if an error was made). ES Examples Used in the Medical Field (9) Rule-based systems: MYCIN, the most well-known ES mentioned above, encodes its information in approximately 500 rules based on the IF-THEN structure. It consists of two parts: data base and inference engine. Data base contains data on the field of expertize, whereas inference engine is more general purpose. In other words, when the content of the data base is changed, the inference engine can still function. This distinction is called EMYCIN and allows the development of similarly structured data-based systems in other subject areas both within and outside of medicine. BLUEBOX and HEADMED can be presented as examples developed in the field of psychopharmacology, and PUFF in the field of pulmonary diseases. In addition, ONCOCIN is an example of MYCIN derivative systems that support oncologists.

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Causal models: CASNET is prepared for the diagnosis of glaucoma eye disease. Diseases are defined as a network of causes and consequences. The system is performed close to a specialist physician. Hypothesis-based systems: PIP has been developed for the diagnosis of edema, and ABEL for the regulation of acid-base and electrolyte balance. Fuzzy ESs Fuzzy ES helps to make logical solutions and inferences within the framework of fuzzy logic rules of fuzzy inputs and outputs in systems with insufficient data. Fuzzy sets and subsets are the basis of fuzzy reasoning. In a classical set theory, an entity is or is not an element of the cluster. If this state is expressed mathematically, “1” is the element of the cluster, and “0” is not the element of the cluster. Clusters in fuzzy reasoning are expanded forms of classical clusters. Each entity in the fuzzy entity cluster has a membership degree. The membership degree of entities can be any value ranging from 0 to 1. In other words, fuzzy logic is a logic system that uses the changing gray levels from the true-false dilemma in order to overcome the challenges occurring while working with indefinite data and results of the symbolic logic (10). Most concepts used in medicine are fuzzy. The fuzzy logic method is suitable for medical applications due to the imprecise nature of medical concepts and the relationships between these concepts. Indefinite medical conditions can be defined with fuzzy sets. Fuzzy logic proposes methods of generating solutions with approximate results. Artificial Neural Networks Artificial neural networks (ANNs) constitute direct, complex, and nonlinear models where the inputs, the independent variables of the system, are associated with the outputs, dependent variables of the system (11). ANN is powerful in computing and information processing. It derives this power from its parallel structure and its ability to learn and generalize. Generalization is the ability to generate appropriate responses to the inputs that the ANN has not encountered in the education or learning process. All these features show that the ANN is capable of solving complex problems. Neuron, the main process element of the ANN, is nonlinear. Therefore, ANN that is formed by the combined cells is also nonlinear, and this feature is spread over the whole network. With this feature, it has become the most important tool in the solution of these nonlinear complex problems (12). In addition, in many problems, it can make more accurate decisions than human specialists. However, when asked, it cannot provide clear responses as an ES does. Another problem of ANN is that it requires an expertize level of use. This situation has prevented the widespread use of ANN in medical practice (7).

CONCLUSION Artificial intelligence has evolved over the years and has made significant progress in medicine. The fact that the AI does not overlook any details and does not forget any information, and that it will review all the possibilities makes it successful. Among these, although ES is preferred since it makes the cause and effect relationship clearer, more complex systems should be created by integrating ANN with fuzzy reasoning in order to overcome the deficiencies.

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In addition, it is not possible to create an ES based on senses. For example, it is both difficult and relative to express the senses, such as taste and smell. The decision to eliminate all diagnostic and therapeutic decisions to the ES still remains unanswered as it brings the question of who will be responsible for the errors. In the present study, it should be emphasized that the purpose of the use of AI in the medical field is not to replace the physician directly but to facilitate the diagnosis and treatment procedure for the physician. However, with the benefits and achievements of health care studies, it is inevitable that it will open a new era in medicine and shed light on more advanced diagnosis and treatment methods. Thus, it can be said that the target will be achieved more quickly in the diagnosis and treatment. Therefore, the cost will decrease.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - S.S.Ç.; Design - S.S.Ç.; Supervision A.Ö.; Data Collection and/or Processing - S.S.Ç.; Analysis and/or Interpretation - S.S.Ç.; Literature Search - S.S.Ç.; Writing Manuscript - S.S.Ç.; Critical Review - A.Ö. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

Çakır and Ötünçtemur. Artificial Intelligence

REFERENCES 1. Available from: http://www-formal.stanford.edu/jmc/whatisai.pdf 2. Nabiyev VV. Yapay Zeka. Ankara: Seçkin Yayınları, 2003. 3. Available from: http://www.aaaipress.org/Classic/Buchanan/buchanan.html 31.09.2007 4. Babalık A, Güler İ. Boğaz Enfeksiyonlarının Teşhis ve Tedavisinde Uzman Sistem Kullanımı. Selçuk Üniversitesi, Teknik Bilimler Meslek Yüksekokulu, Teknik-Online Dergi 2007; 6: 2. 5. Ignizio J. Introduction to Expert System. Houston: McGraw-Hill Inc.; 1991. 6. Available from: http://www.emo.org.tr/ekler/2da8c91ce7b1084_ ek.pdf 7. Bilge U. Tıpta Yapay Zeka ve Uzman Sistemler. Türkiye Bilsim Dernegi Kongresi, 2007. 8. Tosyalı H. Uzman Sistemlerin Yasal Düzenlemelere Uygulanarak Akıllı Veri Tabanlarının Geliştirilmesi, Yüksek Lisans Tezi, Maltepe Üniversitesi. Fen Bilimleri Enstitüsü, İstanbul, 2008. 9. Perry CA. Knowledge bases in medicine: a review. Bulletin of the Medical Library Association, 1990, 78: 271. 10. Kosko B. Fuzzy thinking: the new science of fuzzy logic. New York: Hyperion, 1993 11. Haykin S. Neural networks: A comprehensive foundation. New York: Macmillan College Publishing Company Inc, 1994. 12. Etikan İ, Elbozan Cumurcu B, Çam Çelikel F, Erkorkmaz Ü, Yapay sinir ağları yöntemi ve bu yöntem kullanılarak psikiyatrik tanıların sınıflanması. Tıp Bilimleri Dergisi 2009; 29: 2.

Review

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Artificial Intelligence in Surgery Emin Köse

, Nadi Nazım Öztürk

, Servet Rüştü Karahan

Department of General Surgery, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract To discuss the advantages of transition from laparoscopy to robotic surgery and next generation autonomous robots that will be introduced when integrated with artificial intelligence in surgery. After the usage of the technological products that started with laparoscopic systems in surgery and the advantages it provided, a transition towards robotic surgery was realized, but the desired point could not be reached in robotic surgery. The robots are used as laparoscopic instruments with increased mobility in today. The desired point is the autonomous robots that have the ability to auto-function or independently. Existing robots will be transformed into robots with superior technical features and predictability when integrated with artificial intelligence technology that can perceive the surroundings, recognize problems, implement appropriate action plans and produce solutions for new problems. The practical points that can bring the surgical techniques together with the ethical problems that will be brought together are a matter of discussion. In the near future, it can be foreseen that autonomous robots may be the assistant or rival of surgeons in the operating rooms thanks to the rapid developments in engineering, computer and robotics. The use of artificial intelligence in surgery can save time, decrease medical errors, and achieve better surgical outcomes. However, there is a need for multidimensional algorithms that are still not developed for the production of robots that can undertake the task of the surgeon in order to make critical and ethical decisions. Keywords: Laparoscopic surgery, robotic surgery, artificial intelligence

INTRODUCTION ORCID IDs of the authors: E.K. 0000-0002-0888-2576; N.N.Ö. 0000-0002-6620-0895; S.R.K. 0000-0003-4895-5538. Cite this article as: Köse E, Öztürk NN, Karahan SR. Artificial Intelligence in Surgery. Eur Arch Med Res 2018; 34 (Suppl. 1): S4-S6. Corresponding Author: Emin Köse E-mail: dreminkose@yahoo.com Received: 01.10.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.43043 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Laparoscopic video systems are introduced as the first precursor of the technology in surgery. The use of laparoscopic surgery (LS) began at the beginning of the twentieth century, and it has rapidly developed in the last two decades. In recent years, almost all operations have been performed by laparoscopic technique (1). Lately, robotic surgery (RS) has become widespread, and it has been applied worldwide. The starting point of the RS was the limit of the LS, making the surgeries applicable in a similar way to open surgery. The robots used in surgery are actually used as laparoscopic instruments with increased mobility. We desire to obtain the automatic robots that can be programmed or can independently function (2). The artificial intelligence (AI) technology, which was introduced by Gunn for the diagnostic evaluation of abdominal pain in 1976, is nowadays in use with the algorithms developed in RC with numerous data (3-5). Artificial intelligence has become more popular in different industrial areas. Five million dollars have been spent on AI in 2016 (6). The goal of the AI technology is to design programs that can make their own decisions and carry out the desired task with better efficiency and fewer errors. With the studies that will be conducted by surgeons and data scientists together, it will be possible to see in near future the prototypes of the products using the AI technology in RS. The aim of this review is to explore the use of advanced technology products in surgery and the points that future-generation RS systems can achieve.

REVIEW Laparoscopic surgery was first performed by Hans Jacobaeus in Sweden in 1901. However, after unsuccessful experiences, the first successful LS was the laparoscopic cholecystectomy performed

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by the German surgeon Erich Müche in 1985 (1). Since then, LS has made great progress. Nowadays, although all operations can be performed laparoscopically, RS has started to come to the forefront. The term “robot” comes from the Czech word “robota”, which means the non-living entity that is forced labored. The development of robots is inspired by the drawing book of Leonardo Da Vinci, which is why the first surgical robot was named after him (2). Today, even though the most important subject of discussion for RS is cost, increasing the surgical practice by defining the digital data and integrating AI into robots will gain importance in future (7). The place of AI in science seems to be dependent on its ability to perform the tasks as good as people can or better than they can. Owing to its present applications and its self-improvement ability, it can eliminate human errors in some areas, and can even achieve better results by going beyond human intelligence. However, on the other hand, there are also opposing views suggesting that it will never catch up with human intelligence and analytical thinking (8, 9). Today, AI is used in many different industrial fields to give machines learning ability by developing data algorithms and to develop artificial neural networks, internet-based learning, and computational skills. It is used in health sector by being included in electronic medical records, clinical algorithms, and analyses of image data in pathology and radiology. Moreover, nowadays, we see that AI is used in the ECG analysis, interpretation of arterial blood gas, interpretation of some radiological images such as mammography, and many other medical fields (10). The use of AI in surgery can mainly be listed as the abilities of decision-making and applying surgical techniques during the surgical procedure, but complex surgical procedures, instantaneous complications, and the personal solutions offered by the surgeons to patients prevent the use of AI in surgery (11). The first widespread use of AI is likely to be the strengthening of human performance by computer. In pathology, which is an area that utilizes AI in this way, the error rate in the detection of cancer-positive lymph node has reduced from 3.4% to 0.5% (12). A robot, which is widely used in surgery nowadays, is not fully integrated with AI. It is a high-tech product commanded by surgeons. Three-dimensional high-quality image with robotic technology, increased freedom of movement with articulating hand tools, elimination of vibration, and the possibility of safe suturing in the narrow spaces as in open surgery are among the advantages of RS. The smart tissue autonomous robot, which is the first example of robots assisting surgeon by using the AI technology, can perform intestinal anastomoses more precisely and faster than experienced surgeons can, although it works under surgeon’s control (13). Apart from the robots that assist the surgeon, in autonomous robots equipped with AI, it is aimed to reach a device that monitors all vital signs at the same time during the operation and gives verbal warnings when necessary, analyzes all the current information needed for the moment, performs pathological examination, and determines surgical margins in solid organ tumors, applies appropriate surgical technique with zero margin of error, and calculates the possible postoperative complications, beside only increasing the vision and eliminating hand shivering (14).

Köse et al. Artificial Intelligence

One of the most different ideas on this subject is that soft, fully deformable, and small-sized robots that will be produced with three-dimensional printers can perform the operation by entering into the surgical site from a small incision line (15). With the rapid developments in engineering, computer, and robotics, this technology, which currently seems distant, will go beyond a dream as a groundbreaking method in future. Because existing systems only arrange for the construction and use of medical devices, it will be necessary to decide on the autonomy of the robot and when the robot goes beyond being a device. Considering that there will be improvements in the relationship among the patient, the surgeon, and the robot in future and that there will be cooperation between the surgeon and autonomous robots on the patient, the evaluation of the ethical rules in the scope of the responsibility toward the patient will also be discussed (11).

CONCLUSION The use of AI in surgery can lead to time saving, decrease in medical errors, and better surgical outcomes. However, there is a need for multi-directional algorithms, which have still not been developed, to produce robots that can completely undertake the task of the surgeon because of the necessity of critical and ethical decisions in surgery.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - E.K.; Design - E.K., N.N.Ö.; Supervision - E.K., S.R.K.; Data Collection and/or Processing - E.K., N.N.Ö.; Analysis and/or Interpretation - E.K.; Literature Search - E.K., N.N.Ö.; Writing Manuscript - E.K.; Critical Review - E.K., S.R.K. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1.

Vecchio R, MacFayden BV, Palazzo F. History of laparoscopic surgery. Panminerva Med 2000; 42: 87-90. 2. Hamet P. Artificial intelligence in medicine. Metabolism. W.B. Saunders; 2017; 69: 36-40. 3. Gunn AA. The diagnosis of acute abdominal pain with computer analysis. J R Coll Surg Edinb 1976; 21: 170-2. 4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5953825/ 5. Chand M, Ramachandran N, Stoyanov D, Lovat L. Robotics, artificial intelligence and distributed ledgers in surgery: data is key! Tech Coloproctol 2018; 1-4. 6. Available from: https://www.cbinsights.com/research/artificial-intelligence-startup-funding/ 7. Aruni G, Amit G, Dasgupta P. New surgical robots on the horizon and the potential role of artificial intelligence. Investig Clin Urol 2018; 59: 221. 8. Kahn CE. Artificial intelligence in radiology: decision support systems. Radiographics 1994; 14: 849-61. 9. Siegel E. Artificial intelligence and diagnostic radiology: Not quite ready to welcome our computer overlords. Appl Radiol 2012; 41: 8-9. 10. Miller RA. Medical Diagnostic Decision Support Systems-Past, Present, And Future: A Threaded Bibliography and Brief Commentary. J Am Med Informatics Assoc 2018; 1: 8-27.

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11. Mirnezami R, Ahmed A. Surgery 3.0, artificial intelligence and the next-generation surgeon. Br J Surg 2018; 105: 463-5. 12. Available from: http://arxiv.org/abs/1606.05718 13. Shademan A, Decker RS, Opfermann JD, Leonard S, Krieger A, Kim PC. Supervised autonomous robotic soft tissue surgery. Sci Transl Med 2016; 8: doi: 10.1126/scitranslmed.aad9398.

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14. Camarillo DB, Krummel TM, Salisbury JK. Robotic technology in surgery: Past, present, and future. Am J Surg 2018; 188: 2-15. 15. Wehner M, Truby RL, Fitzgerald DJ, Mosadegh B, Whitesides GM, Lewis JA, et al. An integrated design and fabrication strategy for entirely soft, autonomous robots. Nature 208; 536: 451-5.

Review

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Novel Advances in Oncology Şener Cihan

, Serdar Arıcı

, Ruhper Çekin

Department of Medical Oncology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Novel technological developments are commonly used in oncology practice. The novel approaches contribute to oncologist for screening, diagnosis, treatment, and follow-up periods. Genetic-based tests and liquid biopsies are well-known novel diagnostic techniques especially in breast and lung cancers. Targeted therapies, immune checkpoint inhibitors, invasive treatment modalities, and radioligand therapies are well-known advances in the treatment of cancer. These novel modalities in treatment are dependent on specific conditions especially mutations and receptor status in different cancer types. In this topic, we summarized the new technological advances in screening, diagnosis, treatment, and follow-up practices. Keywords: Oncology, new techniques, diagnosis, treatment

Novel Advances in Oncology Novel technological developments are commonly used in oncology practice. The novel approaches contribute to oncologist for screening, diagnosis, treatment, and follow-up periods. In the present study, we summarized the new technological advances in screening, diagnosis, treatment, and follow-up practices.

Screening - Diagnosis

ORCID IDs of the authors: Ş.C. 0000-0002-3594-3661; S.A. 0000-0003-2018-6554; R.Ç. 0000-0002-7111-8482. Cite this article as: Cihan Ş, Arıcı S, Çekin R. Novel Advances in Oncology. Eur Arch Med Res 2018; 34 (Suppl. 1): S7-S9. Corresponding Author: Şener Cihan E-mail: serdararici@hotmail.com Received: 15.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.72473 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Genetic-Based Tests Stool-based DNA test might be used in patients who had an average risk for colon cancer. The aim of this test is to determine blood and DNA in stool sample. In addition, the sensitivity of this test has been found to be equal to standard colonoscopy. Therefore, the test is recommended to be used every 3 years for screening of colorectal cancer if this test is selected to screen average risk individuals (1). Next-generation sequencing (NGS) uses sequencing of multiple DNA fragments performed in parallel. It is appropriate to consider exome sequencing or targeted NGS gene panels when a large number of pathogenic genes need to be screened (2). Similarly, exome sequencing or whole genome sequencing should be considered when a condition demonstrates high heritability in a family or is suspected to have a genetic basis, but the number of potential candidate genes is large, or responsible gene(s) are unknown. Some gene examples include BRCA1 and BRCA2 if there is a personal or family history of prostate and/or pancreatic cancer, even in the absence of breast or ovarian cancer, screening for inherited causes of gastrointestinal cancers and analyzing tumor tissue to identify genetic abnormalities that may potentially match molecularly targeted therapies. Other available genetic tests in oncology use gene expression rather than gene sequencing to identify molecular signatures in tumors (e.g., Oncotype Dx panels for breast, colon, and prostate cancers). Gene expression profiling determines the level to which a gene is transcribed, as opposed to variations in gene sequence. The Oncotype Dx 21-gene recurrence score is the best-validated prognostic assay and may identify patients who are most and least likely to derive benefit from adjuvant chemotherapy. In addition, the clinical validity of Amsterdam 70-gene prognostic profile (mammaprint) was demonstrated (3).

Cihan et al. Novel Advances in Oncology

Liquid Biopsies While molecular diagnostics have traditionally been performed on biopsies of solid tumor tissue, blood-based tests or so-called “liquid” biopsies are gaining popularity as they provide the opportunity to genotype in a less invasive and less expensive manner and may offer a chance to monitor the molecular features of cancer through the course of treatment or predict relapse after adjuvant treatment (4). In 2018, the joint review of the American Society of Clinical Oncology and the College of American Pathologist stated that there is not enough evidence in early stage cancer for the clinical value of circulating tumor DNA (ctDNA) in treatment and follow-up periods or detection of residual tumor (5). There are currently two US Food and Drug Administration-approved ctDNA tests for patients with lung cancer in both the estimated glomerular filtration rate (EGFR) mutation-positive setting. It is likely that as more data emerge, the use of liquid biopsies to assess other molecular abnormalities will become more widespread (6). Treatment Novel treatment agents that are advancing by technological developments are widely used in oncology practice. Targeted tyrosine kinase, checkpoint inhibitors, invasive treatment modalities, and radioligand therapies are well-known advances in the treatment of cancer. Tyrosine kinase inhibitors (TKIs) targeting EGFR are erlotinib, gefitinib (first-generation agent), afatinib, dacomitinib (second-generation agent), and osimertinib (third-generation agent) in nonsmall cell lung cancer (NSCLC). All of these agents improved the outcome in NSCLC. Newer data demonstrate improved progression-free survival (PFS) outcomes with front-line osimertinib compared with gefitinib or erlotinib. In addition, these agents have more tolerable side effect profiles than standard chemotherapy (7-8). A group of patients with NSCLC have fusion oncogene EML4ALK. Alectinib, crizotinib, and ceritinib are agents that target ALK. Alectinib had a reduction in risk of progression or death of 53% (HR 0.47, 95% CI 0.34-0.65), with a median PFS not reached versus 11.1 months for those receiving crizotinib at a median follow-up of approximately 18 months. The median PFS rates were 25.7 months with alectinib and 10.4 months with crizotinib (HR 0.50) based on an independent review. The overall survival (OS) results are not yet mature (9). In HER2 (member of the tyrosine kinase receptor family) positive breast cancer, trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine are used widely for different points of the disease. Bevacizumab, aflibercept, ramucirumab (targeting vascular endothelial growth factor (VEGF)), cetuximab, and panitumumab (targeting EGFR) are monoclonal antibodies combined with chemotherapy in metastatic colorectal cancer (10). Vemurafenib, dabrafenib, and encorafenib (inhibitors of the BRAF serine/threonine protein kinase pathway) combinations with MEK inhibitors (trametinib, cobimetinib, and binimetinib) are used in BRAF mutation-positive metastatic malignant melanoma and improved outcomes in both PFS and OS (11).

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VEGFs (TKIs), including cabozantinib, pazopanib, sunitinib, axitinib, lenvatinib, and sorafenib, are commonly used in renal cell carcinoma. Sunitinib and pazopanib are the most preferred agents due to strong evidences (12). Programmed cell death protein 1 (PD-1) is a transmembrane protein expressed on T cells, B cells, and natural killer cells and can bind to PD-1 and 2 ligands. This binding inhibits the apoptosis of tumor cells and decreases the number of effector T cells. Immune checkpoint inhibitors block this interaction by inhibiting PD-1 or programmed death-ligand 1 (PD-L1). There are two PD-1 inhibitors (pembrolizumab and nivolumab) and three PD-L1 inhibitors (atezolizumab, avelumab, and durvalumab) for approval for cancer treatment. Non-surgical invasive treatment options include radiofrequency ablation, microwave ablation, laser ablation, high-intensity focused ultrasound ablation, and cryoablation. These options are most commonly used in liver metastasis and primary liver tumors (13). Peptide receptor radioligand therapies, especially those with radiolabelled somatostatin, are increasingly used in neuroendocrine tumors (14). Sipuleucel-T is an autologous dendritic cell therapeutic vaccine produced to increase the T cell response against prostatic acid phosphatase in patients with metastatic prostate cancer. This vaccine is prepared from the mononuclear cells of the patient. Then, as ex vivo, these cells stimulated with an immunogen fusion protein consist of recombinant prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Thereafter, these stimulated cells are infused back into the patients (15).

Peer-review: Externally peer-reviewed. Author Contributions: Concept - Ş.C., S.A., R.Ç.; Design - Ş.C., S.A., R.Ç.; Supervision - Ş.C.; Data Collection and/or Processing - S.A., R.Ç.; Analysis and/or Interpretation - Ş.C., S.A., R.Ç.; Literature Search - Ş.C., S.A., R.Ç.; Writing Manuscript - Ş.C., S.A., R.Ç.; Critical Review - Ş.C. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1.

Dhaliwal A, Vlachostergios PJ, Oikonomou KG, Moshenyat Y. Fecal DNA testing for colorectal cancer screening: Molecular targets and perspectives. World J Gastrointest Oncol 2015; 7: 178-83. 2. Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med 2014; 370: 2418-25. 3. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 2018; 379: 111-21. 4. Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 2017; 545: 446-51. 5. Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, et al. Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol 2018; 36: 1631-41.

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Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the Evolution of Non-Small-Cell Lung Cancer. N Engl J Med 2017; 376: 2109-21. 7. Lee CK, Brown C, Gralla RJ, Hirsh V, Thongprasert S, Tsai CM, et al. Impact of EGFR inhibitor in non-small cell lung cancer on progression-free and overall survival: a meta-analysis. J Natl Cancer Inst 2013; 105: 595-605. 8. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018; 378: 11325. 9. Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-SmallCell Lung Cancer. N Engl J Med 2017; 377: 829-38. 10. Hurwitz HI, Tebbutt NC, Kabbinavar F, Giantonio BJ, Guan ZZ, Mitchell L, et al. Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. Oncologist 2013; 18: 1004-12. 11. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition

Cihan et al. Novel Advances in Oncology

alone in melanoma. N Engl J Med 2014; 371: 1877-88. 12. Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, et al. Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol 2014; 32: 480-7. 13. Choi D, Lim HK, Kim MJ, Lee SH, Kim SH, Lee WJ et al. Recurrent hepatocellular carcinoma: percutaneous radiofrequency ablation after hepatectomy. Radiology 2004; 230: 135-41. 14. Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29: 2416-23. 15. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24: 3089-94.

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Innovations in Genetic Medicine: A Journey in Time Biray Ertürk1

, Burçin Pehlivanoğlu2

Department of Medical Genetics, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Department of Pathology, Adıyaman University Training and Research Hospital, Adıyaman, Turkey

Abstract The relationships between science and technology have been disputed for almost a century now. As they appear to accelerate each other, the major effect of the technological innovation on genetic medicine has been mainly observed following the completion of the Human Genome Project. Genetic medicine, also known as medical genetics, currently focuses on many aspects of medicine including genomic analyses and clinical services, such as genetic counseling, diagnosis, and management of genetic and hereditary disorders or genetic aspects and management of neoplastic diseases. This review provides an overview of the history of genetic medicine and an insight to the current application of genomic technology into clinical practice. Keywords: Medical genetics, innovation, technology

INTRODUCTION

ORCID IDs of the authors: B.E. 0000-0002-0348-6267; B.P. 0000-0001-6535-8845. Cite this article as: Ertürk B, Pehlivanoğlu B. Innovations in Genetic Medicine: A Journey in Time. Eur Arch Med Res 2018; 34 (Suppl. 1): S10-S12. Corresponding Author: Biray Ertürk E-mail: birayerturk@gmail.com Received: 28.09.2018 Accepted: 24.24.10.2018 DOI: 10.5152/eamr.2018.07279 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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Genetic analyses have become crucial in patient management as a result of advances in the field in the last two decades, following the mapping of the human genome in 2003. Since then, many disease-causing and/or related genes have been explored, and the introduction of genomic medicine, also known as personalized medicine, was an important milestone, especially for patients with cancer and their relatives. Genetic medicine, also known as medical genetics, currently focuses on many aspects of medicine including genomic analyses as well as clinical services, such as genetic counseling, diagnosis, and management of genetic and hereditary disorders or genetic aspects and management of neoplastic diseases. This review discusses the innovative genetic techniques and their use in daily routine practice. Evolution of Clinical Cytogenetics Cytogenetics studies the chromosomes by making their structure visible under a microscope and identifying their size, banding pattern, and centromere locations, thus demonstrating the chromosomal defects, such as deletions, translocations, or inversions. Chromosomal analysis has been widely used for prenatal diagnosis to diagnose patients with congenital anomalies and/or mental retardation (1) and diagnosis and management of patients with cancer. It can be performed on cells obtained from different tissues, including blood, fetal blood and tissues, chorionic villi, amniotic fluid cells, skin, bone marrow, tumor samples, and effusion fluid. In 1956, Tijo and Levan (2) conducted the first study on cytogenetics. They established the normal human chromosome number as 46. In the 1960s, cytogenetic studies accelerated with the discovery that fetal cells could be obtained through amniocentesis to identify chromosomal abnormalities (3). While high-resolution banding techniques improved the chromosome analysis (4), submicroscopic chromosomal alterations remained to be undetected until the discovery of fluorescence in situ hybridization (FISH) in the early 1980s, the beginning of the molecular cytogenetics era. Fluorescent DNA or RNA probes targeting specific chromosomal locations allowed the assessment of fluorescent-dyed signals to be visualized under a fluorescent microscope. FISH does not require cell culture and can directly use fresh or paraffin-embedded interphase nuclei for rapid evaluation compared with conventional cytogenetics metaphase

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karyotype analysis (5). In addition, it has become a widely used diagnostic tool in both genetic and neoplastic diseases, providing simultaneous evaluation of multiple abnormalities in multiple locations (e.g., centromeric and subtelomeric). Fluorescence in Situ Hybridization (FISH) can also be used in preimplantation genetic diagnosis (PGD), which is a procedure that identifies embryonal genetic defects prior to implantation. It is performed in in vitro fertilization of embryos (IVF embryos) and allows for the detection of the abnormality before embryo transfer so that only unaffected embryos are transferred back (6). The indications for PGD can be divided into five categories: chromosome abnormalities, sexing for X-linked disease, single gene defects, preimplantation genetic screening, and social sexing (7). In 1990, the first PGD was performed by Handyside et al. (8) for the detection of X chromosome-linked diseases in two couples known to be at risk of transmitting adrenoleukodystrophy and X-linked mental retardation. Although they used polymerase chain reaction (PCR) to detect the defects, FISH has also been widely applied for the preimplantation detection of chromosome abnormalities, allowing the evaluation of many chromosomes at the same time, with up to 15 chromosome pairs in a single cell (9). However, FISH has several technical limitations, including hybridization failure (lack of signal), signal overlap, signal splitting, poor probe hybridization, cell loss, and variable cell fixation (10). Currently, PCR, comparative genomic hybridization (CGH), single-nucleotide polymorphism (SNP) microarray analysis (10), and next-generation sequencing (NGS) can be used for PGD. In 1992, CGH, also known as chromosomal microarray analysis (CMA), a technique combining cytogenetics with molecular genetics, was introduced by Kallioniemi et al. (11) to detect DNA amplification in tumor cells. CGH (or CMA) is based on competitive hybridization of tumor DNA and normal DNA using traditional metaphase chromosome preparation, and a few years after the first report, DNA microarrays replaced the traditional preparation (array CGH) (12). It is generally used for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), or multiple congenital anomalies (MCAs) (13), offering a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype, primarily because of its higher sensitivity for submicroscopic deletions and duplications (13). CMA is a high-resolution technique that allows the detection of microdeletions and/or duplications, which are called copy number variants (CNVs), but it is expensive to be used in routine screening and is not able to detect truly balanced chromosomal rearrangements or low-level mosaicism (1, 13). Therefore, an algorithmic approach should be employed based on the clinical indication, and it would be more appropriate to use traditional (G-banded) karyotype analysis to investigate for chromosomal syndromes, such as Down syndrome or balanced rearrangements. It is also noted that a CNV can be of no medical consequence. CGH (CMA) is also one of the most commonly used methods in PGD, and an SNP-based array has been developed to improve the resolution recently (10). Evolution of Molecular Genetics Molecular genetics focuses on the structure and function of genes at a molecular level. Gene amplification is the most widely used procedure for molecular analyses. In 1983, Kary Mullis de-

ErtĂźrk and PehlivanoÄ&#x;lu. Innovations in Genetic Medicine

veloped the PCR technique, an amplification technique enabling the DNA replication many times. He was awarded the 1993 Nobel Prize in Chemistry along with Michael Smith. The automation of the PCR technique was one of the major improvements to begin the Human Genome Project, and the project also led to a significant improvement in the sequencing technology (14). First-generation sequencing (Sanger sequencing) has analyzed only individual samples of DNA, whereas NGS, also known as massively parallel sequencing or second-generation sequencing, has provided a thorough and rapid sequencing of large amounts of genetic material with reasonable costs. NGS is now widely used for both clinical and research purposes. NGS technology successfully provides a genome-wide investigation of causal variants in single gene disorders and complex genomic landscapes of many diseases (14). Whole genome sequencing (WGS) and whole exome sequencing (WES) basically use the NGS method. In WGS, the sequence of most of the DNA content comprising the entire genome of an individual can be determined, whereas exomes are sequenced in WES. Exome is the component of the genome that encodes proteins and comprises approximately 1% of the genome. Protein coding segments are referred to as exons and exomes can also include non-coding exons. Therefore, WES provides the identification of the DNA sequence of most of these protein-encoding exons and may include some DNA regions that encode RNA molecules that are not involved in protein synthesis. It is a cheaper and more effective method than WGS, considering that most disease-causing mutations are detected within the protein-encoding regions of the genome. Noninvasive prenatal testing (NIPT), a screening method to detect fetal aneuploidy by analyzing small fragments of fetal cell-free DNA circulating in maternal blood, is another application of NGS technology. NIPT is most commonly used for prenatal diagnosis of trisomy (trisomy 21 (Down syndrome), trisomy 18, or trisomy 13) or sex chromosome abnormalities. However, NIPT is not yet recommended as a routine prenatal screening test, especially in lowrisk pregnancies, due to lower positive predictive value in low-risk pregnancies/populations, being relatively expensive, and offering a limited diagnostic window. On the other hand, it is a promising prenatal diagnostic test and will probably improve with the technological advances. The utility of microRNAs in NIPT may help the improvement of NIPT, given that the increased maternal plasma levels of some microRNAs have been shown in women carrying a fetus with Down syndrome in a recent study (15). Another recent discovery particularly affecting tumor genetics is the implementation of liquid biopsy into the clinical practice. A liquid biopsy may be defined as obtaining circulating tumor cells, tumor-derived cell-free DNA, or other compounds from body fluids, mostly from peripheral blood, and it can be used for diagnosis, follow-up, and management of diseases, with neoplasms in most cases. While it is a highly advanced non-invasive diagnostic tool using novel molecular techniques, such as PCR or NGS, there are still disadvantages and limitations, such as the fragmentation of cell-free DNA, RNA instability, the low concentrations of certain analytes in body fluids, and the confounding presence of normal and aberrant DNAs and RNAs (16). A third-generation sequencing technique, also known as longread sequencing, that reads nucleotide sequences at the single molecular level appears to have the potential to open a new era

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in medical genetics. However, this technology still needs to be improved to be used in routine clinical practice.

CONCLUSION Science and technology go hand in hand. Technological innovations lead to genomic discoveries, and genomic discoveries fuel more technological advancements to fulfill the need in clinical practice. While a multidisciplinary approach is of utmost importance to select the most useful genetic tests and approach in patient management, computational genomics appears to be an essential part of future research, as it is used to analyze, process, and store all the data obtained from projects by using mathematics and computer techniques to develop algorithms or models.

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6. 7.

10.

Peer-review: Externally peer-reviewed.

11.

Author Contributions: Concept - B.E.; Design - B.E., B.P.; Supervision - B.P.; Data Collection and/or Processing - B.E.; Analysis and/or Interpretation - B.P.; Literature Search - B.E., B.P.; Writing Manuscript - B.E., B.P.; Critical Review - B.E., B.P.

12.

Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1.

Gonzales PR, Carroll AJ, Korf BR. Overview of Clinical Cytogenetics. Curr Protoc Hum Genet 2016; 89: 8-13. 2. Tijo H, Levan A. The chromosome number of man. Hereditas 1956; 42: 1-6. 3. Prabhu Britto A, Ravindran G. A review of cytogenetics and its automation. J Med Sci 2007; 7: 1-18. 4. Yunis JJ. High resolution of human chromosomes. Science 1976; 191: 1268-70.

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Hu L, Ru K, Zhang L, Huang Y, Zhu X, Liu H, et al. Fluorescence in situ hybridization (FISH): an increasingly demanded tool for biomarker research and personalized medicine. Biomark Res 2014; 2: 3. Carlson LM, Vora NL. Prenatal Diagnosis: Screening and Diagnostic Tools. Obstet Gynecol Clin North Am 2017; 44: 245-56. Harper JC, Wilton L, Traeger-Synodinos J, Goossens V, Moutou C, SenGupta SB, et al. The ESHRE PGD Consortium: 10 years of data collection. Hum Reprod Update 2012; 18: 234-47. Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990; 344: 768-70. Mackie Ogilvie C, Scriven PN. Meiotic outcomes in reciprocal translocation carriers ascertained in 3-day human embryos. Eur J Hum Genet 2002; 10: 801-6. Chen CK, Yu HT, Soong YK, Lee CL. New perspectives on preimplantation genetic diagnosis and preimplantation genetic screening. Taiwan J Obstet Gynecol 2014; 53: 146-50. Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 1992; 258: 818-21. Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes, Chromosomes & Cancer 1997; 20: 399-407. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: 749-64. Durmaz AA, Karaca E, Demkow U, Toruner G, Schoumans J, Cogulu O. Evolution of genetic techniques: past, present, and beyond. Biomed Res Int 2015; 2015: DOI: 10.1155/2015/461524. Erturk B, Karaca E, Aykut A, Durmaz B, Guler A, Buke B, et al. Prenatal Evaluation of MicroRNA Expressions in Pregnancies with Down Syndrome. Biomed Res Int 2016; 2016: DOI: 10.1155/2016/5312674 Finotti A, Allegretti M, Gasparello J, Giacomini P, Spandidos DA, Spoto G, et al. Liquid biopsy and PCR-free ultrasensitive detection systems in oncology (Review). Int J Oncol 2018; 53: 1395-434.

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Technological Innovations in Intensive Care Unit Esra Akdaş Tekin Namigar Turgut

, Ömür Gökkaya

, Seray Türkmen

, Şule Vatansever

Department of Anesthesiology and Reanimation, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Intensive care units (ICUs) are equipped with advanced technology within the hospital and are specially structured, providing 24-hour support every day of the week. These units have health personnel experienced in the monitoring of severe illnesses. As a result of developments in science and technology, the techniques used in ICUs have also improved. Keywords: Intensive care, technology, cerebral oximetry

INTENSIVE CARE UNIT AND TECHNOLOGICAL INNOVATIONS Intensive care units are special units in which patients are closely monitored and treated due to a life-threatening critical disease. Respiratory failure, severe infections, heart attack, sudden cardiac arrhythmias, coma, shock, serious trauma and accidents, intoxications, and post-operative special conditions requiring a close follow-up are the most common reasons for hospitalization in the ICUs.

ORCID IDs of the authors: E.A.T. 0000-0002-0976-7369; Ö.G. 0000-0002-9162-8770; S.T. 0000-0002-3542-3906; Ş.V. 0000-0002-5387-0734; N.T. 0000-0003-0252-3377. Cite this article as: Akdaş Tekin E, Gökkaya Ö, Türkmen S, Vatansever Ş, Turgut N. Technological Innovations in Intensive Care Unit. Eur Arch Med Res 2018; 34 (Suppl. 1): S13-S18. Corresponding Author: Namigar Turgut E-mail: namigarturgut@gmail.com Received: 09.10.2018 Accepted: 28.10.2018 DOI: 10.5152/eamr.2018.62207 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Intensive care units are specially structured units equipped with advanced technology within the hospital, which provides 24-hour support every day of the week. In these units, health personnel experienced in the monitoring of severe diseases are assigned (1). As a result of developments in science and technology, the techniques used in ICUs have also improved. TELE-ICU: It stands for the remote management of ICUs. Efficient decisions can be made from a high-tech command center by connecting to the ICUs through audio-visual/video conferencing and monitoring. All patient data are reflected to the monitors in real time by means of intensive care automation, which provides 24/7 data monitoring and are then recorded (Figure 1). Furthermore, • It shortens the duration of stay in the intensive care. • It contributes to the reduction of mortality rates. • It increases the bed usage cycle in ICUs. • It helps to minimize medication errors and other medical errors. • It provides economic efficiency. (2) Mixed Venous or Central Venous Oxygen Saturation (SvO2/ScvO2): It is the parameter that reflects the balance between the arterial oxygen delivery and oxygen usage of tissues. Considering the formula DO2=CO×CaO2 (DO2, oxygen delivery to the tissue; CO, cardiac output; CaO2, oxygen content of arterial blood), the difference between the amounts of venous and arterial oxygen can only be taken as the difference between oxygen saturations when unchanging variables such as fixed numbers and hemoglobin in the two systems are removed from the equation. In this case, the cardiac output is directly related to the difference in venous and arterial oxygen saturation. The normal range of mixed venous saturation is 65%-70%. Mixed venous saturation decreases when the oxygen delivery decreases or oxygen consumption of the tissue increases. Again, when the cardiac output is reduced or circulation impaired, a decrease is observed in mixed venous saturation because the oxygen extraction will increase. The monitoring of mixed venous oxygen saturation allows early detection of tissue hypoxia, and it is important. In patients

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with circulatory and cardiac problems, mixed venous saturation monitoring is particularly important in the titration of inotropic therapy. Although there are catheters that can perform continuous monitoring of mixed venous saturation, they are not widely used. Mixed saturation monitoring is performed with intermittent blood gases in most centers (3). Pulse Index Contour Continuous Cardiac Output (PICCO): This is a device that can continuously measure the cardiac output through the femoral artery with the pulse contour method, without any need for pulmonary artery intervention. The measurement process starts with the standard Stewart-Hamilton thermodilution technique, and it allows continuous cardiac output to be moni-

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tored by pulse contour analysis over the artery trace. In addition, it also measures the values of the intra-thoracic blood volume and extra-vascular lung water and provides an idea on cardiac pre-load and lung fluid. Therefore, it is particularly useful for monitoring the fluid balance (volume management) of patients under the mechanical ventilation support. PICCO with a central venous catheter and a femoral artery is an advanced hemodynamic monitor used to follow up patients with cardiac problems (Figure 2) (4). Echocardiography: After the widespread use of ultrasonography in ICUs, the application of echocardiography by intensive caregivers without a cardiologist has also become widespread. Moreover, the guidelines for this examination, which can be called cardiac ultrasonography, have been published. The parameters evaluated in this examination are the inferior vena cava diameter, prediction of preload from the right and left ventricle end-diastolic diameters, right ventricular/left ventricular functions, regional wall motion abnormalities, pericardial effusion and tamponade, and valvular structure status (5). Lactate Measurement: It is the intermediate metabolite pyruvate occurring due to glycolysis in the cytoplasm, and it is converted into lactic acid under anaerobic conditions. There are two types of lactic acidosis. Type A: There is a decrease in tissue perfusion or oxygenation. Lactate production increases due to tissue hypoxia in circulatory and respiratory failure or diseases impairing the Hb-oxygen transport.

Figure 3. MeasurementTranscutaneous of CO2 Figure 1. TELE-ICU

Figure 2. PICCO-Plus System (The permission of PULSION Medical Systems SE.)

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Figure 4. Near-infrared spectroscopy

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Type B: The main cause is not tissue hypoxia, and the use of oxygen by the tissues is impaired due to a primary cause. Liver diseases, thiamine deficiency, gluconeogenesis, or factors impairing oxidative phosphorylation cause a decrease in the lactate utilization. Since an increased lactate level is significant in diagnosing, demonstrating hypoxia and hypoperfusion, or predicting early mortality, lactate measurement with blood gas devices is highly valuable. Transcutaneous CO2 Measurement: It is performed with a small electrode placed on the skin. The heating wire inside the electrode increases the permeability of the epidermis and increases the gas diffusion through the capillary. Although it is a practical method, it should be confirmed by the arterial blood gas or ETCO2 if the patient is intubated because conditions such as hypothermia, hemodilution, and low arterial blood pressure affect the optimum measurement conditions of the device, such as an access to the appropriate temperature, high capillary perfusion, and calibration (Figure 3) (6).

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Near-Infrared Spectroscopy (NIRS): NIRS is a technique measuring the amount of absorption caused by chromophore molecules-such as oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb), cytochrome-c oxidase (CCO), and myoglobin-while the near-infrared light is passing through the tissues (7). The measurement of O2Hb and HHb concentration changes in tissues by The NIRS technique was first performed by Jöbsis et al. in 1977. It was guiding the measurement of tissue oxygenation, and NIRS was begun to be used to evaluate the oxygen status of the brain tissue (8). Cerebral oximetry is the name of the method in which the regional cerebral oxygen saturation values are measured noninvasively and continuously using the NIRS technique (Figure 4) (9). BIS Monitoring: As is known, sedation is very important in ICUs. It is necessary to adapt the patients to mechanical ventilator treatment and to achieve the optimal level of sedation for their hemodynamic stabilization. Inadequate sedation and sudden changes in consciousness disturb the patient’s comfort and may lead to negative consequences such as inadequate ventilation, a

Figure 5. BIS-VISTA Monitoring system b

Figure 6. BIS Complete 2 Channel Monitor-Covidien

Figure 7. a, b. Extracorporeal Membrane Oxygenation (ECMO). (a) Veno-venous Extracorporeal Membrane Oxygenation (b) Veno-arterial Extracorporeal Membrane Oxygenation

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hypertension, and tachycardia. On the other hand, excessive sedation may adversely affect the cardiovascular functions and lead to a prolonged mechanical ventilation. Moreover, it increases the risk of developing physical dependence and tolerance. For these reasons, the sedation dose should be regularly adjusted with

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continuous monitoring of the patientâ&#x20AC;&#x2122;s sedation level (10). BIS is an EEG parameter. BIS monitoring is used to measure changes in the consciousness of sedated patients in a continuous, objective, and reliable way. The BIS index is a number ranging from 0 to 100, and it is correlated with significant clinical conditions during an anesthetic agent administration. While BIS values around 100 indicate that the patient is awake, the value of 0 indicates an isoelectric EEG. In prospective studies, it has been reported that keeping the BIS index values between 40 and 60 during the stay in the ICU provides an adequate hypnotic effect (Figure 5, 6) (11). Extracorporeal Membrane Oxygenation (ECMO): ECMO is the process of a temporary support of respiratory and/or cardiac functions in patients who do not respond to conventional therapy. Blood taken from the patient with an external pump through cannulas and placed in the large vessels is passed through the membrane (oxygenator), and gas exchange is provided. It is then given to the patient again. It is usually applied in two ways for pulmonary (veno-venous) and cardiopulmonary (veno-arterial) support (12). Veno-venous Extracorporeal Membrane Oxygenation: VV-ECMO is the most common technique in patients without severe cardiac dysfunction, but with isolated respiratory failure, severe ARDS, and refractory hypoxemia or hypercapnia. Its purpose is to provide oxygenation, to rest the lungs, and to reduce the damage caused by mechanical ventilation.

Figure 8. Mechanical ventilator devices

Figure 9. Hemodiafiltration device

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Veno-arterial Extracorporeal Membrane Oxygenation: VA-ECMO can be used for both the left and right ventricular failure. For the return of oxygenated blood, the cannulation of the ascending aorta or femoral artery is required. By bypassing these, VA-ECMO reduces the pulmonary artery pressure, increases systemic perfusion, and provides higher PaO2 levels compared to VV-ECMO. VA-ECMO functions parallel to the heart and lungs (Figure 7. a, b.) (13). While the advantages of ECMO are in pro-

Figure 10. Critocool-pro

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viding the support to both the heart and lungs, enabling the arterial and venous cannulation from a single site, providing good oxygenation even at low flow, and being independent of cardiac functions, its disadvantages include the risk of embolization due to thrombi particles present in the system, the requirement of carotid ligation, a possible transfer of hyperoxygenated blood flow to the brain, and bleeding with coagulopathy. Mechanical Ventilator Devices: Ventilators are devices that enable breathing by sending the gas flow to the patient’s airways in a controlled manner when spontaneous respiration required to sustain life is threatened. Unlike old machines, which in the simplest way only provide mandatory breathing to the patient, new ventilator devices offer many mode options that can adjust each stage of the breathing. The options such as continuous mandatory ventilation; assist control; synchronous intermittent mandatory ventilation; continuous positive airway pressure ventilation; volume-controlled ventilation; pressure-supported ventilation, pressure-controlled ventilation; and very new modes including volume-assured pressure support, volume-supported, pressure-regulated volume control, proportional assist ventilation, and bilevel positive airway pressure ventilation allow us to select the ventilation type specific to each patient group. While only fiO2, the tidal volume, number of breaths, and pressure settings can be adjusted on the old machines, the settings of PEEP, triggering, the inspiratory/expiratory ratio, flow rate, inspiration time, expiration time, and the peak inspiratory pressure can be adjusted at present (Figure 8). Noninvasive mechanical ventilation (NIV) is a preferred method of ventilation in appropriate patients due to the reasons such as avoiding complications of endotracheal intubation, preventing nosocomial infection and ventilator-related infections, reducing the need for sedation, and reducing the hospital stay. In the past, separate devices were required for this method; however, it is possible to perform NIV with new modes added to the mechanical ventilators used in ICUs in recent days. Since the mask is used during NIV, there is almost always air leakage. However, in these new machines, leak compensation is sensitive, and sufficient and ventilation support tolerates leakage. Although conventional NIV machines have a single tube, intensive care ventilators have double tubes, which prevents carbon dioxide retention, which is very important for NIV patients (14-18). Hemodiafiltration: Renal insufficiency requiring renal replacement therapy is a commonly encountered condition in intensive care patients. Compared to conventional intermittent hemodialysis, continuous renal replacement therapy (CRRT) has the advantages of less disturbance to hemodynamic stability, a better control of the intravascular volume, and less electrolyte acid-base disturbances. CRRT develops in parallel with the development of technology in this field. Thanks to the development of pumps and sets, it has become possible to carry out a longer and more effective procedure. CRRT is named according to the type of vascular intervention and whether diffusion or convection is used. Although the CRRT techniques can be divided into arterio-venous and veno-venous techniques according to the catheter entry site, no arterio-venous method is used anymore (Figure 9) (19-21). Hypothermia: In patients with appropriate indications, after providing spontaneous circulation following cardiopulmonary resuscitation, the body temperature is reduced to 32-34°C within

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the first 4-6 hours to obtain a successful neurological return, and after the target temperature is reached, it is kept stable at this level for 12-24 hours (18 hours on average). This process is called therapeutic hypothermia. By inserting a special balloon catheter from the femoral or jugular vein, continuous cold water is pumped for circulation through a special hypothermia device from the balloons on the catheter, and it is aimed to reduce the body temperature by cooling the circulating blood. After reaching the target temperature, the heating process is started after 18 hours on average (12-24 hours). Heating is a slow process in contrast to the induction phase. With the help of the device, the heating is done in an average of 6 hours with a temperature of <0.5°C increased per hour. This slow heating process prevents imbalances that may occur in hemodynamics, metabolism, and electrolyte values (22). It is accepted that the early initiation of therapeutic hypothermia in selected patients after cardiac arrest prevents the chemical reactions caused by reperfusion injury, contributes to the neurological recovery, and may hinder the progression of damage. It is important that the cooling process is initiated as early as possible after patient responding to resuscitation and that the patient is kept at an appropriate temperature, which is performed with the latest hypothermia devices (Figure 10) (23, 24).

Peer-review: Externally peer-reviewed. Author Contributions: Concept - E.A.T., Ö.G., S.T., Ş.V., N.T.; Design E.A.T., N.T.; Supervision - E.A.T., Ö.G., Ş.V., N.T.; Data Collection and/ or Processing - E.A.T., Ö.G., S.T., N.T.; Analysis and/or Interpretation E.A.T., N.T.; Literature Search - E.A.T., Ö.G., S.T., Ş.V., N.T.; Writing Manuscript - E.A.T., N.T.; Critical Review - E.A.T., Ö.G., S.T., Ş.V., N.T Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. 2.

Available from: http://www.toraks.org.tr Thomas EJ, Lucke JF, Wueste L, Weavind L, Patel B. Association of telemedicine for remote monitoring of intensive care patients with mortality, complications, and length of stay. JAMA 2009; 302: 26718. 3. Kesici S, Bayrakçı B. Yoğun Bakımda Monitorizasyonda Yenilikler. Türkiye Klinikleri J Pediatr 2011; 7: 43-8. 4. Litton E, Morgan M. The PiCCO monitor: a review. Anaesth Intensive Care 2012; 40: 393-409. 5. Mazraeshahi RM, Farmer JC, Porembka DT. A suggested curriculum in echocardiography for critical care physicians. Crit Care Med 2007; 35: 431-3. 6. Conway A, Tipton E, Liu WH, Conway Z, Soalheira K, Sutherland J, Fingleton J. Accuracy and precision of transcutaneous carbon dioxide monitoring: a systematic review and meta-analysis. Thorax 2018; pii: thoraxjnl-2017-211466. 7. Steppan J, Hogue CW Jr. Cerebral and tissue oximetry. Best Pract Res Clin Anaesthesiol 2014; 28: 429-39. 8. Jobsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters. Science 1977; 198: 1264-7. 9. Toet MC, Lemmers PM. Brain monitoring in neonates. Early Hum Dev 2009; 85: 77-84.

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10. Carrasco G. Instruments for monitoring intensive care unit sedation. Crit Care 2000; 4: 217-25. 11. Gan TJ, Glass PS, Windsor A, Payne F. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 1997; 87: 808-15. 12. Bayar MK, Kosovalı DB. ECMO. Güncel Göğüs Hastalıkları Serisi 2018; 6: 93-103. 13. Akarsu Ayazoğlu T, Didem Onk. Erişkin ARDS Hastalarında ECMO, J Turk Soc Intens Care 2015; 13: 95-106. 14. Noninvaziv Mekanik Ventilasyon Uygulamaları. 2017 TÜSAD Kitapları- Editor: Uzm. Dr. Serpil ÖCAL. Türkiye Solunum Araştırmaları Derneği. 15. Oto J, Chenelle CT, Marchese AD, Kacmarek RM. A comparison of leak compensation in acute care ventilators during noninvasive and invasiveventilation: a lung model study. Respir Care 2013; 58: 2027-37. 16. Garnier M, Quesnel C, Fulgencio JP, Degrain M, Carteaux G, Bonnet F, et al. Multifaceted bench comparative evaluation of latest intensive care unit ventilators. Br J Anaesth 2015;115: 89-98. 17. Jaber S, Bellani G, Blanch L, Demoule A, Esteban A, Gattinoni L, et al. The intensive care medicine research agenda for airways, invasive

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18.

19.

20. 21. 22.

23. 24.

and noninvasive mechanical ventilation. Intensive Care Med 2017; 43: 1352-65. Marjanovic NS, De Simone A, Jegou G, L’Her E. A new global and comprehensive model for ICU ventilator performances evaluation. Ann Intensive Care 2017; 7: 68. Rauf AA, Long KH, Gajic O, Anderson SS, Swaminathan L, Albright RC. Intermittent hemodialysis versus continuous renal replacement therapy for acute renal failure in the intensive care unit: an observational outcomes analysis. Intensive Care Med 2008; 23: 195-203. Karakoç E. Sürekli renal replasman tedavileri. Yoğun Bakım Dergisi 2007; 7: 240-6. Dikmen Y. Renal replasman tedavisi: ne zaman, nasıl, nereye kadar? Türk Yoğun Bakım Derneği Dergisi 2010; 8: 18-27. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549-56. Açıkalın A, Gülen M, Acehan S, Sebe A. Terapötik Hipotermi. Arşiv 2011; 1: 20-35. Alshimemeri A. Therapeutic hypothermia after cardiac arrest. Ann Card Anaesth 2014; 17: 285-91.

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Innovations in Orthopedic Surgery: How to Change Good to Perfect? Haluk Çabuk Department of Orthopedics and Traumatology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Innovation has always been an obvious part of orthopedic surgery. Orthopedics has been moving toward excellence through robotic surgeons, stem cell applications, scaffolds, and minimally invasive methods from a surgical branch that has already achieved good results thanks to plates, intramedullary nails, prostheses, and arthroscopy, which entered our daily practice in the last century. Keywords: Stem cell, robotic surgery, humanization, scaffold

INTRODUCTION Orthopedics is one of the departments where technological innovations and innovative technologies are frequently used. The wide range of operations starting from trauma-induced fractures in orthopedic surgery to arthroplasty or soft tissue reconstruction in sports surgery, and the patient portfolio starting from the newborn period to the old patients, always push the orthopedists to be innovative and perfectionist. When the high expectations of patients with fracture and elective surgical patients are added to this, it becomes a necessity for the orthopedics department to be a pioneer in adapting new technologies to medicine.

ORCID ID of the author: H.Ç. 0000-0002-1413-2149. Cite this article as: Çabuk H. Innovations in Orthopedic Surgery: How to Change Good to Perfect? Eur Arch Med Res 2018; 34 (Suppl. 1): S19-S21. Corresponding Author: Haluk Çabuk E-mail: halukcabuk@hotmail.com Received: 12.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.24008 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Unfortunately, the periods of war have become the periods when the most rapid developments occurred in orthopedics. The concepts of “antisepsis”, “recurrent debridement”, and “primary and delayed wound healing” that were put forward after the World War I (1), and the internal fixation methods that rapidly became popular after World War II, established the basis of modern orthopedics. Minimally invasive procedures made a breakthrough in orthopedics, especially with the use of arthroscopy to view the knee joint 100 years ago in 1918, and with the popularization of arthroscopic methods after the 1950s (2). Another important development in the last century was to find a solution to the hip and knee arthrosis seen in about half of the population, thanks to total hip and total knee prosthesis. Compilation We can say that orthopedic surgery is at a new turning point, especially with the introduction of tissue engineering and robotic surgery into the field of orthopedics after the 1990s. With the use of three-dimensional printers in the medical field, orthopedic surgery shows a shift from being implant-based to being biological-based. Bone scaffolds of large bone defects that are formed in 3D printers are produced to provide a new bone tissue. However, in the recent years, the transformation rates of bone scaffold into original bone and knitting rates have considerably increased with the use of dipyridamole in the content of these scaffolds (3). This newly formed bone has the same durability and biological properties as the biomechanically undamaged bone has (4). Another place where three-dimensional printers are used is polyurethanes- or collagen-based meniscus scaffolds developed for the patients who become symptomatic after simple meniscus injury, or whose complaints do not recover after arthroscopic meniscectomy, but who are not suitable

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for knee replacement. These implants have been in use since approximately 10 years, and they have proven to be useful in symptomatic patients after meniscectomy in large meta-analyses (5, 6). Studies suggest that the results of collagen-based meniscus implants are better (7). Thanks to these implants, patients who have completely lost the meniscus tissue can return to their normal daily lives with a simple arthroscopic procedure, and their need for prosthesis may be delayed. Another important innovation in sports traumatology is the “humanized” animal ligaments. Many different graft alternatives have been used to prevent donor site morbidity, which is one of the difficulties during ligament reconstruction. However, the xenografts used until now caused swelling and early tendon re-ruptures due to the activation of the autoimmune system. Alternatively, allografts and synthetic grafts can be used. However, because of the low biocompatibility of synthetic grafts, the results are not satisfactory. The use of allografts was limited because their durability was low when they were not fresh-frozen, and their cost was high when they were fresh-frozen. However, the antigens in the xenografts obtained from pigs or cattle can be completely cleaned with the new “humanization” methods, and they do not produce autoimmune responses in the recipient (8). We expect that these animal-derived xenografts will soon be placed on orthopedic shelves. This humanization process can also be used to obtain animal-derived bone grafts for bonebased cancers such as osteosarcoma or for filling large bone defects developing secondary to trauma. Large cartilage defects are one of the most important problems of joint surgery. Massive osteochondral allografts are currently the most popular methods for filling these defects. Instead of the use of massive osteochondral allografts, the use of these newly humanized shell xenografts with pluripotent stem cells was submitted for approval to the FDA in the US. Grudon and Yamanaka won the Nobel Prize in the field of physiology and medicine in 2012 (9). They were able to obtain immature pluripotent stem cells by reprogramming somatic mature cells. This study is very close to eliminating ethical and cost problems such as obtaining the immature pluripotent stem cells from the cord blood or storing. In large cartilage defects of our degenerated joints, and in spinal cord injuries or degenerated intervertebral discs, stem cell therapies embedded in scaffolds that are taken from only a small skin biopsy and are programmed to be transformed into cartilage or nerve tissue again and are taken from 3D printers are the future of reconstructive orthopedics. Even today, stem cell applications are successfully used to create hyaline-like cartilage for cartilage defects. Stem cells obtained from adipose tissue or bone marrow aspiration are currently applied to the defect site with surgical methods. However, in the near future, the treatment with the stem cells delivered to the troubled region through selective arterial stem cell applications appears to be possible. Especially in avascular necrosis of the femoral head, studies show that stem cells given to the medial femoral circumflex artery feeding the femoral head stop the progression of the disease and provide near-total healing (10). In spinal surgery, two important developments give hope for the future. The first of these is that Alpa-2-macroglobulin protein in

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the blood is able to inhibit the proteases that cause destruction of the disc in degenerative disc disease that affects millions of people in the world today (11). This finding will shed light on the development of new drugs and methods in the treatment of degenerative disc disease in the future. Another important development is the trial of elastic deformable plaques in spinal surgery. Especially the failure to provide fusion in cervical surgery constitutes a significant problem. Currently, 46% faster fusion can be achieved with these elastic plates in studies on animal models (12). Although there are regulations in the field of materiology and tribology in prosthetic surgery every year, the actual innovation is the introduction of robotic navigation systems into prosthesis implantation. It has been shown that surgeons decrease the margin of error through the use of these navigation systems in centers where prosthesis surgery is not performed intensively, and thus they increase prosthetic survival (13, 14). In addition to clinical benefits, robotic systems will also reduce the burden on the health-care system by reducing the transfer costs of patients and materials. The decreasing number of health personnel compared to the increasing and aging population every year will be insufficient to provide adequate health services. Orthopedists will soon be able to perform the surgery with distant connections and without even going to the hospital or possibly from a completely different country, and they will not need anything other than a few arms of the robot. Although it seems to be very futuristic at the moment, four to five sets of prostheses containers and a small pile that will be constituted by possible prosthesis sizes are required for a standard knee prosthesis operation, which increases both the inventory costs and hospitals’ outgoings. A robotic system can do this only with one to two burr tips, and it can determine which size of an implant the patient will need before the operation. Data-tracking systems in these robotic systems will provide a wide range of patient data, and these data will contribute to the perfection of the technique and the training of next-generation surgeons (15). The future of not only orthopedics but also medicine lies in the software. Thanks to the more intelligent computer softwares, the diagnosis of many diseases will be possible without the need for a doctor. For example, in the US, the FDA has approved the use of artificial intelligence in the detection of wrist fractures, and IBM has been working to develop this artificial intelligence software. In addition, companies such as Osso VR (USA) have introduced virtual reality simulations for the use in surgical training. These new softwares are evolving to provide a wide set of benefits ranging from the better adjustment of patient records and follow-up to the prevention of errors that could occur in nurse orders, and from the stock capabilities to the charging for services.

CONCLUSION Although orthopedic surgery has come a long way with the widespread use of arthroplasty, internal bone fixation and arthroscopy in the last 100 years, it has reached a new milestone with the development of artificial intelligence, robotic surgeries, and stemcell-based therapies.

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Peer-review: Externally peer-reviewed. Conflict of Interest: The author has no conflicts of interest to declare. Financial Disclosure: The author declared that this study has received no financial support.

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Banovetz JM. The development of orthopedics in 20th century warfare. The Iowa Orthopaedic Journal 1997; 17: 32-46. 2. Jackson RW. From the scalpel to the scope: the history of arthroscopy. Baylor University Medical Center Proceedings 1996; 9: 77-9. 3. Bekisz JM, Flores RL, Witek L, Lopez CD, Runyan CM, Torroni A, et al. Dipyridamole enhances osteogenesis of three-dimensionally printed bioactive ceramic scaffolds in calvarial defects. J Craniomaxillofac Surg 2018; 46: 237-44. 4. Ishack S, Mediero A, Wilder T, Ricci JL, Cronstein BN. Bone regeneration in critical bone defects using three-dimensionally printed β-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 2017; 105: 366-75. 5. Monllau JC, Poggioli F, Erquicia J, Ramírez E, Pelfort X, Gelber P, et al. Magnetic Resonance Imaging and Functional Outcomes After a Polyurethane Meniscal Scaffold Implantation: Minimum 5-Year Follow-up. Arthroscopy 2018; 34: 1621-7. 6. Patel JM, Ghodbane SA, Brzezinski A, Gatt CJ Jr, Dunn MG. Tissue-Engineered Total Meniscus Replacement With a Fiber-Reinforced Scaffold in a 2-Year Ovine Model. Am J Sports Med 2018; 46: 1844-56.

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Houck DA, Kraeutler MJ, Belk JW, McCarty EC, Bravman JT. Similar clinicaloutcomes following collagen or polyurethane meniscal scaffold implantation: a systematic review. Knee Surg Sports Traumatol Arthrosc 2018; 26: 2259-69. 8. Zaffagnini S, Grassi A, Marcheggiani Muccioli GM, Roberti Di Sarsina T, Raggi F, Benzi A, et al. Anterior cruciate ligament reconstruction with a novel porcine xenograft: the initial Italian experience. Joints 2015; 3: 85-90. 9. Omole AE, Fakoya AOJ. Ten years of progress and promise of induced pluripotent stem cells: historical origins, characteristics, mechanisms, limitations, andpotential applications. Peer J 2018; 11: e4370. 10. Mao Q, Jin H, Liao F, Xiao L, Chen D, Tong P. The efficacy of targeted intraarterial delivery of concentrated autologous bone marrow containing mononuclear cells in the treatment of osteonecrosis of the femoral head: a five year follow-up study. Bone 2013; 57: 509-16. 11. Huang B, Chen J, Zhang X, Wang J, Zheng Z, Shan Z, et al. Alpha 2-Macroglobulin as Dual Regulator for Both Anabolism and Catabolism in the Cartilaginous Endplate of Intervertebral Disc. Spine 2018; 22: doi: 10.1097/BRS.0000000000002852. 12. Ledet EH, Sanders GP, DiRisio DJ, Glennon JC. Load-sharing through elastic micro-motion accelerates bone formation and interbody fusion. Spine J 2018; 18: 1222-30. 13. Goradia VK. Computer-assisted and robotic surgery in orthopedics: where we are in 2014. Sports Med Arthrosc Rev 2014; 22: 202-5. 14. Marchand RC, Sodhi N, Bhowmik-Stoker M, Scholl L, Condrey C, Khlopas A, et al. Does the Robotic Arm and Preoperative CT Planning Help with 3D Intraoperative Total Knee Arthroplasty Planning? J Knee Surg 2018; 15: doi: 10.1055/s-0038-1668122. 15. Parsley BS. Robotics in Orthopedics: A Brave New World. J Arthroplasty 2018; 33: 2355-7.

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Technology Innovations in Urology Recep Burak Değirmentepe

, Emre Can Polat

, Alper Ötünçtemur

Department of Urology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Technological developments have entered our daily lives, and they have made many innovations possible in urology. Over the last decade, robotic surgical technology has had significant impact on clinical practice. Techniques that require microsurgical precision and advanced reconstructive skills and inaccessible areas of surgery can be optimized with the help of robotic surgery. This new robotic technology has led to the use of the laparoscopic surgeon in lifting the limitations of the urologist in daily practice. The source data obtained by the imaging methods are visualized in two dimensions. With finite processing tools and algorithms, it is possible to produce multiplane reformations and three-dimensional views of the anatomy. Anatomical three-dimensional models are used to help complex operations, implement precise training procedures, and understand the patient’s preoperative surgery better. In addition to technological improvements, standard percutaneous nephrolithotomy operations were evolved into miniperc, microperc, and ultraminiperc, which were also suitable for stone volume. Thus, operation-related injuries in the kidney were reduced. Proliferation of the mpMRG system with recent advances in technology has allowed us to examine the prostate in detail. With the introduction of the mPMRG-derived data in the prostate biopsy, steps have been taken to directly remove the prostate biopsy sample from the tumor tissue. This method allows the biopsy sample to be directly taken from the area, which is a radiologically suspected cancer. The future of medical treatments goes beyond “minimally invasive surgery.” A more complex approach involving new variables, such as new imaging, gene coding, molecular biology, nanotechnology, and tissue environment is certainly ahead. Keywords: Innovation, technology, urology ORCID IDs of the authors: R.B.D. 0000-0002-2875-5750; E.C.P. 0000-0001-5254-2563; A.Ö. 0000-0002-0553-3012. Cite this article as: Değirmentepe RB, Polat EC, Ötünçtemur A. Technology Innovations in Urology. Eur Arch Med Res 2018; 34 (Suppl. 1): S22-S24. Corresponding Author: Recep Burak Değirmentepe E-mail: rebudet54@gmail.com Received: 09.08.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.47966 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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INTRODUCTION Although technological developments have entered our daily lives, there have been many innovations also in the field of urology. The developing technology creates different usage areas. We have tried to summarize the surgical use of robotic technology, which is one of primary innovations of current medicine in urological diagnosis and treatment, the use of 3D printers, the process of taking tissue from tumoral focus with the MR fusion biopsy for diagnosis, and the use of developments of minimization in endoscopic surgeries in urology. The Use of Robotics in Urology Robotic surgery is often described as revolutionary. Over the past decade, it has been surgically applied. Eagerness to renew the technology, consideration of the laparoscopic surgery’s limitations, easy acceptance of robotic technology by surgeons, and attractive marketing has resulted in the use of the robot in our daily practice. The long-term results of procedures performed with robotic surgery technique are published in the literature, and a critical analysis of these data continues to define the role of robots in clinical practice. Surgical application of robotic technology has been developed over the last 30 years, but clinical practice has had a significant impact in the last 10 years. Surgical techniques that require microsurgical sensitivity and advanced reconstructive skills and inaccessible surgical sites can be optimized by robotic surgery. Advanced robotic surgical systems, such as Da Vinci are effectively equipped with three-dimensional (3D) and high-resolution (HD) visualization, advanced manual skill, ergonomic position, elimination of vibrations, and scalability of movements. To overcome

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some of the limitations of traditional laparoscopy, urologists have now embraced surgical robots. In many parts of the world, the robot-assisted urological surgeries have become everyday clinical practice (1). Experienced centers in robotic surgeries applied clinical application to other minimally invasive urological surgeries. In addition to its widespread use in oncologic surgery, pyeloplasty, ureteral reimplantation, appendicovesicostomy, and augmentation enterocystoplasty are increasingly being performed with robotic assistance. The long-term results will describe the role of robots in these operations (1). Minimally invasive laparoscopic techniques have replaced many open urological surgeries. The addition of robotic assistance has enabled surgeons to progress and overcome many technical limitations of traditional laparoscopy. The long-term results of robot-assisted urological surgery are comparable to those of traditional open surgical methods. According to currently collected data, they have been shown to be associated with fewer complications. Surgical robots continue to develop everyday. The robotic engineers are working hard to synthesize and evaluate robotic platforms, to make equipment smaller, to develop robotic surgery experience, and to develop flexible tools and new technologies to broaden the practice (1). Use of 3D Printers in Urology Rapid advances in medical imaging have revolutionized the field of medicine. Computed tomography (CT), magnetic resonance imaging (MRI), and other imaging methods noninvasively allow for a more detailed view of the anatomy of an object and to perform field and volume measurements on it. This plays an active role in helping scientists and physicians almost communicate with anatomical structures and learn potentially life-saving information. Today, the role of medical imaging is not limited to simple visualization and observation of anatomical structures. It is used in areas such as disease diagnosis, advanced surgery planning and simulation, and radiotherapy planning (2). The source data obtained by any imaging method is typically visualized in two dimensions. It is possible to produce multi-planar reformations and 3D views of anatomy with finishing tools and algorithms. The process chain from image acquisition to the production of a 3D rapid prototype model consists of three stages. It will be discussed in detail in the following sections: “Image capture,” “processing after image,” and “3D printing” (3). In urology, 3D printing is used for patient information, assistant training, and preoperative planning. The 3D models of the pelvicalyceal system structure and stone volume were formed by using the data obtained from the CT images particularly before percutaneous nephrolithotomy (PNL) operations. These models provide additional information about the different possible operative approaches, and they are useful in the rehearsal and modification of the operative technique (4). Anatomically, the creation of 3D models that are anatomically identical to the patient’s kidney collecting system demonstrates that it is a more effective way of learning for assistants than the traditional imaging methods are. It is evident that the assistants can understand kidney anatomy, calyx number and placement, and preference of appropriate access by using models creat-

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ed by 3D printing method better than preoperative evaluation performed by using traditional imaging models. It increases self-confidence of the assistant during the surgery (5). 3D printing, when combined with medical imaging, is a powerful diagnostic tool. It contributes to assistant education. Anatomical 3D models are visually used to assist in complex surgeries, to perform delicate procedures for educational purposes, and to help patient better understand the process preoperatively. As both medical imaging and 3D printer technology continue to progress, new opportunities for combined usages in urology will arise (2). Minimization in Urological Surgery Over the past decade, the indications for PNL have seen a paradigm shift. In previous years, the PNL was performed for complex multiple calculus and large-volume stones, such as staghorn calculi. Several studies confirmed that reducing the size of the tract decreased potentially percutaneous surgical complications (6). This led to the concept of the miniaturization in urological surgery. Smaller sheaths, smaller endoscopes, and miniaturization of the tools in the development of energy resources emerged. The miniaturization of the surgical instruments was also responsible for the paradigm shift in the PNL operations. These miniature instruments and accessories have eliminated the need to expand the path by more than 20 Fr (7). With technological developments, the standard PNL operations have been evolved into miniperc, microperc, and ultimately ultraminiperc in ones with suitable stone volume. The use of tiny instruments has been very useful especially in the pediatric patient group. Thus, postoperative bleeding rates and the damage caused by the operation in the kidney decreased. The most important component of the ultraminiperc, which has the narrowest canals, is a new 6-Fr miniperoscope. This miniperoscope can be passed through an 11-14-Fr metal sheath. The stones are broken by laser. One-step dilatation can be performed under ultrasound or fluoroscopy control. A unique feature of this technique is the availability of the lateral canal on the metal sheath. This can be used for irrigation and/or removal of fragmented stones (8). Standard PNL is used in the treatment of stones larger than 2 cm in size. New techniques with miniperc are suitable for stones 1.5-2 cm in size. Microperc and ultraminiperc can be suitable for stones <1.5 cm in size. They are also suitable for special conditions, such as diverticular stones and pediatric mid-size stones (7). MR-Transrectal Ultrasound (TRUS) Fusion Biopsy Prostate biopsy is the standard method to diagnose prostate cancer, which constitutes 15% of all cancers diagnosed among men in the world. A standard prostate biopsy is the systematic tissue sampling from the prostate under the guidance of TRUS. Tissue is taken from at least 12 foci. However, this method has its limitations. Cancerous tissue cells cannot be obtained from randomly taken samples. In addition to the possibility of standard biopsy to overlook cancer, it may also not detect “clinically insignificant cancer,” which does not cause problems to the patient throughout life (9). With the development of technologies in recent years, the increased use of multiparametric prostate magnetic resonance imaging (mpMRI) system has enabled the prostate to be examined in detail. With the adaptation of the data obtained by mpMRG

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to prostate biopsy, steps were taken to take the prostate biopsy directly from the tumoral tissue. The most advanced method in this regard is MR-TRUS fusion biopsy. In this method, the images of the patient who underwent mpMRI are processed with computer software programs, and a 3D prostate is created. Then, the data are transferred to the TRUS device, where the biopsy is performed using a special biopsy platform and software. The images obtained from the TRUS device used during the biopsy are given a 3D form by the same device, and the MRI and TRUS images are overlapped to perform the process of fusion. With the help of a robotic arm, samples are taken from the areas determined with the help of MR and TRUS images and marked. This method allows us to take biopsy directly from the area having radiologically suspected cancer, and to minimize the likelihood of the detection of clinically insignificant cancer (10).

CONCLUSION We live in a world with fast and compelling changes. Technological developments come and go, but robotics technology will continue to remain in the practice of medical procedures. In addition, robotic applications at this point, miniaturizations in surgical instruments, 3D technologies, and innovations in imaging methods represent the infancy of technology, and they are open to growth. The technological future developments of these innovations can be scaled to potentially unimaginable heights. We expect much more advanced robotic interfaces and even robots combined with imaging and energies, which aim to provide accurate and reliable treatments to be precisely targeted with biogenetic information. The future of medical treatments goes beyond the “minimally invasive surgery” and a more complex approach that includes new variables, such as new imaging, gene code, molecular biology, nanotechnology, and tissue environment is certainly ahead of us.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - R.B.D.; Design - E.C.P.; Supervision - A.Ö.; Data Collection and/or Processing - E.C.P.; Analysis and/or Interpretation - A.Ö.; Literature Search - E.C.P.; Writing Manuscript - R.B.D.; Critical Review - A.Ö

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Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

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Cathelineau X, Sanchez-Salas R, Sivaraman A. What is next in robotic urology? Curr Urol Rep 2014; 15: 460. 2. Atalay HA, Değirmentepe RB, Bozkurt M, Can O, Canat HL, Altunrende F. 3D Teknolojinin Tıpta ve Üroloji’de Kullanım Alanları. Endoüroloji Bülteni 2016; 9: 65-71. 3. Rengier F, Mehndiratta A, Von Tengg-Kobligk H, Zechmann CM, Unterhinninghofen R, Kauczor HU, et al. 3D printing based on imaging data: Review of medical applications. Int J Comput Assist Radiol Surg 2010; 5: 335-41. 4. Gadzhiev N, Brovkin S, Grigoryev V, Tagirov N, Korol V, Petrov S. Sculpturing in urology, or how to make percutaneous nephrolithotomy easier. J Endourol 2015; 29: 512-7. 5. Atalay HA, Ülker V, Alkan İ, Canat HL, Özkuvancı Ü, Altunrende F. Impact of Three-DimensionalPrinted Pelvicalyceal System Models on Residents’ Understanding of Pelvicalyceal System Anatomy before Percutaneous Nephrolithotripsy Surgery: A Pilot study; J Endourol 2016; 30: 1132-7. 6. Kukreja R, Desai M, Patel S, Bapat S. Factors affecting blood loss during percutaneous nephrolithotomy: prospective study. J Endourol 2004 18: 715-22. 7. Ganpule AP, Bhattu AS, Desai M. PCNL in the twenty-first century: role of Microperc, Miniperc, and Ultraminiperc. World J Urol 2015; 33: 235-40. 8. Desai J, Zeng G, Zhao Z, Zhong W, Chen W, Wu W. A novel technique of ultra-mini- percutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. Biomed Res Int 2013: 490793 9. Mowatt G, Scotland G, Boachie C, Cruickshank M, Ford JA, Fraser C, et al. The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging technique sinaiding the localisation of prostate abnormalities for biopsy : a systematic review and economic evaluation. Health Technol Assess 2013; 17: 1-281. 10. Tyson MD, Arora SS, Scarpato KR, Barocas D. Magnetic resonance-ultrasound fusion prostate biopsy in the diagnosis of prostate cancer. Urol Oncol 2016; 34: 326-32.

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Technological Advancements in Nuclear Medicine and Molecular Imaging Levent Güner

, Kemal Ünal

, Erkan Vardareli

Department of Nuclear Medicine, Acıbadem University School of Medicine, İstanbul, Turkey

Abstract As in most other specialties, technological advancements had their share in nuclear medicine. New synthesis equipment lets departments locally synthesize new radiopharmaceuticals (rfs), to diagnose new pathologies, and treat new conditions. More specific, more sensitive and newer rfs pave the way to diagnosing newer pathologies. On the other hand, new hardware and software increased the image acquisition time and the resolution of images. Once only a scientific interest for few centers, artificial intelligence is now more widespread, more commercialized, from working on improving image quality to diagnosing diseases as well as-and even better than-expert physicians. Keywords: Technological advancements, nuclear medicine, pet, gamma camera

INTRODUCTION

ORCID IDs of the authors: L.G. 0000-0001-8442-1600; K.Ü. 0000-0003-4023-7531; E.V. 0000-0001-9993-4468. Cite this article as: Güner L, Ünal K, Vardareli E. Technological Advancements in Nuclear Medicine and Molecular Imaging. Eur Arch Med Res 2018; 34 (Suppl. 1): S25-S29 Corresponding Author: Levent Güner E-mail: leventguner@yahoo.com Received: 12.11.2018 Accepted: 23.11.2018 DOI: 10.5152/eamr.2018.27247 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Developments in technology have let the Nuclear Medicine Departments synthesize new radiopharmaceuticals (rts); image and treat new pathologies; acquire new Positron emission tomography (PET) and gamma cameras with smaller, faster, and more efficient detectors with sharper resolutions, and in more convenient positions for the patient. New software has also increased the speed of acquisition and image sharpness and detail, and it helped to reduce the patient exposure to radiation, sometimes even complementing physicians in diagnosing of diseases. New Radiopharmaceuticals As of 2018, there are approximately 50 rts approved by the Food and Drug Administration, and of these, 17 are Technetium 99m labeled. Yttrium 90 and Lutetium 177 are used for treatment; Xenon is used for lung studies; N13-Ammonia , Rubidium 82, and Thallium 201 are used for cardiac imaging; Samarium 153 and Strontium 89 are used for bone pain palliation; Iodine-labeled rfs are commonly used for thyroid and for renal imaging; Gallium 68 is used for neuroendocrine imaging and other applications that are obsolete now; and all-favorite oncology probe fluorodeoxyglucose is also used for dementia imaging and cardiac imaging. Most of these rts have a well-established clinical application and a relatively long history and clinical experience. Inside and outside this list, there are some less used but important agents that shed some light on the future of nuclear medicine. Prostate Cancer C11 Choline reflects the speed of cell wall synthesis, and for some time, it played a role in suspected prostate cancer recurrence detection (Figure 1), but it was soon replaced by Ga68-labeled prostate specific membrane antigen (PSMA) antibodies. PSMA, not exactly specific, although first documented in a prostate cell culture approximately 30 years ago, have been efficiently targeted recently. Still not 100% sensitive nor 100% specific, it is currently by far the best agent to detect the lymph node involvement or finding sites of recurrence, and it is possibly as effective as multiparametric prostate magnetic resonance imaging (MRI) to detect clinically significant prostate cancer. Fluorine 18-labeled synthetic amino acid derivative fluciclovine (Axumin, Blue Earth Diagnostics) competes with PSMA for the same setting, but preliminary studies favor the PSMA targeting (1).

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While fluciclovine has been introduced into the NCCN guidelines, there has been no even application from any producer to have PSMA agents approved, possibly due to regulatory and commercial issues. The latest European urology guidelines discuss the PSMA imaging in staging and post-surgical and post-radiotherapy recurrence of prostate cancer (2, 3). Dementia One group of tracers that major pharmaceutical companies have invested in are the amyloid-seeking agents, florbetaben (Piramal, Neuraceq), florbetapir (Elly Lilly, Amyvid), and flutemetamol (GE Healthcare, Vizamyl, Figure 2). Imaging for the amyloid has shown that some patients without Alzheimer’s had an amyloid build up, even in some apparently normal aging subjects, hence lowering the positive predictive value. On the other hand, a negative amyloid scan (i.e., no significant amyloid deposition) effectively rules out Alzheimer’s disease (4). Although these tracers have not gained firm integration into guidelines for the diagnosis of Alzheimer’s disease, there are three clinical situations where amyloid imaging is appropriate; the atypical age of onset, atypical presentations of Alzheimer’s, and unexplained minimal cognitive impairment (5). Brain Tumors Several rts have emerged to image brain gliomas, and researchers have accumulated clinical evidence on the benefits and limitations of each. There are two properties of rfs that create the image of a brain tumor: transport through the blood-brain barrier and metabolism in tumor cells (Figure 3). While malignant brain tumors accumulate FDG F18 as elsewhere in the body, a strong and variable uptake by the brain gray matter limits the use of this tracer. Also, F18-labeled compounds have the advantage of production outside the facility and easier transport, in contrast to carbon-11-labeled compounds that need to be produced on site. The group of tracers composed of large neutral amino acids (i.e., C11 MET-methionine-, F18 FET-fluoroethyltyrosine-, C11 AMT-alphamethyltryptophan, F18 FDOPA) provide better differentiation of benign versus malignant lesions, even between low-grade versus high-grade gliomas. The extent of the uptake of these tracers reflects tumoral extension and provides complementary information to the MRI-enhanced region (6). In addition, time-variant uptake of FET may provide prognostication further than the 1p19q deletion or the IDH mutation status of tumor (7) (Figure 4). Proliferation markers such as F18 FLT-fluorothymidine and C11 Choline have also been used, where their sensitivity is slightly lower than amino acid tracers to detect malignant gliomas, and they do not have a significant uptake in low-grade gliomas. Still, they provide similar prognostication and post-RT/post-surgical follow-up of gliomas as the amino acid tracers. Targeting biopsy of brain tumors have been consistently shown to be more accurate using information provided by amino acid tracers. They show the most malignant part, which in turn determines the prognosis. GTVs from amino acid PET scans can be used for radiotherapy planning, in conjunction with MRI GTV, expecting better clinical outcomes. Another agent, F18 Fluoromisonidazole shows tissue hypoxia, and these regions of tumor

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are more radioresistant. Targeting these regions with higher radiotherapy doses is tempting. For therapy monitoring, especially amino acid tracers seem more immune to the effects of pseudoprogression and pseudoresponse, which is a significant problem in MRI imaging. New Radionuclide Therapies Therapy of thyroid cancer, Graves’ disease, and hyperactive nodules with radioactive iodine (I131) has been in the field of interest of nuclear medicine for decades. In recent years, there have been advances in palliation of bone metastases with alpha-emitting radionuclides, local therapies of hepatic tumors, and systemic therapies of prostate cancer and neuroendocrine tumors. The key point of alpha-emitting radionuclides is that the tissue penetration of these particles is very short, preserving healthy tissues and irradiating tumor cells with a high energy transfer. Ra223 is an important alpha-emitting radionuclide, which is primarily used for the treatment of prostate cancer bone metastases. Injecting beta-emitting particles through the hepatic artery is an important treatment choice for unresectable primary hepatic tumors and liver metastases. Labeling glass microspheres or resin microspheres with Y90 is a good alternative especially for liver-limited unresectable disease. The terms selective internal radiation therapy and transarterial radioembolization are commonly used to define this therapy. Ho166 is also a promising radionuclide in this field. The concept of theranostics became popular with the advance of the Ga68 PET/CT imaging. Personalized therapy and the use of appropriate agent, as well as the appropriate dose, are the key facts of this term. A combination of therapy and diagnostics form this concept. Ga68 PSMA avid prostate cancer metastases and Ga68 DOTATATE avid neuroendocrine tumor lesions can be treated with Lu-177-labeled PSMA and Lu177-labeled DOTATATE, respectively. The Ga68 imaging guides the therapy dose and potential utility of Lu177 therapies. Developing new radionuclides such as Ac225 also seem promising in therapy. New Hardware After reports showing a significant contribution of myocardial perfusion SPECT studies to medical radiation and increased awareness of radiation in medical and nonmedical community, the medical device/software manufacturers raced to bring new technology to address the issue. In gamma cameras, the solid-state cadmium zinc telluride detectors (CZT) instead of traditional NaI crystals brought an improved sensitivity to detect photons. This let physicians use less of the rts (less radiation) and less imaging time. Radiation exposure was reduced 2-4 times in addition to quicker and more comfortable procedures (Figures 5 and 6). New reconstruction algorithms from manufacturers promise resolution recovery, decreased image noise, scatter and attenuation corrections, altogether to decrease necessary radioactivity and study times (8). These improvements also came with innovations in detection physics, sometimes in the form of moving collimators to focus on the organ to be imaged, collecting only the information from the

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GĂźner et al. Technological Advancements in Nuclear Medicine

Figure 1. Choline PET. Pelvic lymph node metastasis of prostate cancer

Figure 2. Negative and positive amyloid PET scans with flutemetamol

Figure 4. FET and MRI images of glioma tectors (1 to 3 in number) needed to turn to create tomography images. Recent introduction of a gamma camera with 12 detectors will be able to create PET-like 3D images of a whole-body gamma camera scan (Figure 7).

target volume of interest.

A conventional PET scanner images 10-30cm at each bed position. After acquiring required counts from each position, the bed advances, and this continues until required parts of the body, typically head to thighs, are imaged, taking approximately 10-15 minutes. A recent development was introduction of a whole-body PET scanner that can image a whole body in under a minute. It is still under construction, but it may greatly decrease the radiation exposure and increase lesion to background ratios (9) (Figure 8).

Positron emission tomography always enjoyed the inherent creation of 3D images with a 360-degrees gantry and detectors completely surrounding the patient, while gamma camera de-

New Software and Artificial Intelligence Even before its recent popularity, the artificial intelligence (AI) was present in molecular imaging, evaluating bone and renal scans.

Figure 3. Mechanisms of uptake for radiopharmaceuticals for brain tumor imaging

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However, it was mostly single-center produced and not commercialized. Thanks to the already massive technical knowledge built up in myocardial perfusion imaging, reconstructing, detecting borders of myocardium, aligning images, quantifying its perfusion, and millions of SPECT scans performed in the world, this subfield was ready for deeper learning. Previous studies mentioned AI algorithms matching physicians in disease detection. This year, researchers using a multi-institution database comprising about 20,000 patient data, reported that AI predictions were better than those of expert physicians (10). Another study reports development of software that predicts survival from an index of metastasis burden of prostate cancer patients from their bone scans (11). Artificial intelligence may also help reduce the radiation exposure of patients. A group of researchers trained AI starting from

Figure 7. GSpectrum dynamics, veriton gamma camera

Figure 5. Spectrum Dynamics D-SPECT gamma camera with CZT detectors

Figure 8. Whole-body PET scanner under development

Figure 6. GE Discovery NM 530C with CZT detectors and focused collimators

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Figure 9. The low dose image in top row, center, left corner original image, NLM, BM3D and AC-Net are alternative methods compared with the proposed AI trained recreated image. Zoomed patches on the right half

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Güner et al. Technological Advancements in Nuclear Medicine

an ultralow dose PET image-1/100 to 1/200th of normal dose-to create a high quality image that could then be evaluated visually or quantitatively by physicians (12) (Figure 9).

Another AI was trained and diagnosed dementia from the FDG PET and amyloid scans, 2 years before the onset of symptoms for amyloid scans (13).

CONCLUSION The future looks bright and exciting for nuclear medicine/molecular imaging. The new pharmaceuticals open up new horizons, and we may be able to treat, even cure, new diseases. With new cameras and better, quicker detectors, images are sharper, acquisitions are faster, and radiation burden on patients is reduced. AI may prove to be an important aid to physicians.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - L.G.; Supervision - E.V.; Writing Manuscript - L.G., K.Ü., E.V.; Critical Review - E.V.

Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

10.

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Calais J, Fendler WP, Herrmann K, Eiber M, Ceci F. Comparison of Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a Case Series of 10 Patients with Prostate Cancer Recurrence. J Nucl Med 2018; 59: 78994. Mottet N, Bellmunt J, Bolla M, Briers E, Cumberbatch MG, De Santis M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017; 71: 618-29. Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol 2017; 71: 630-42.

11.

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13.

Morris E, Chalkidou A, Hammers A, Peacock J, Summers J, Keevil S. Diagnostic accuracy of (18)F amyloid PET tracers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 2016; 43: 374-85. Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Appropriate use criteria for amyloid PET: a report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement 2013; 9: 1-16. Santoni M, Nanni C, Bittoni A, Polonara G, Paccapelo A, Trignani R, et al. [11C]-Methionine Positron Emission Tomography in the Postoperative Imaging and Followup of Patients with Primary and Recurrent Gliomas. ISRN Oncol 2014; DOI: doi: [10.1155/2014/463152]. Thon N, Kunz M, Lemke L, Jansen NL, Eigenbrod S, Kreth S, et al. Dynamic 18F-FET PET in suspected WHO grade II gliomas defines distinct biological subgroups with different clinical courses. Int J Cancer 2015; 136: 2132-45. Ben-Haim S, Kennedy J, Keidar Z. Novel Cadmium Zinc Telluride Devices for Myocardial Perfusion Imaging-Technological Aspects and Clinical Applications. Semin Nucl Med 2016; 46: 273-85. Cherry SR, Jones T, Karp JS, Qi J, Moses WW, Badawi RD. Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care. J Nucl Med 2018; 59: 3-12. Slomka PJ, Betancur J, Liang JX, Otaki Y, Hu LH, Sharir T, et al. Rationale and design of the REgistry of Fast Myocardial Perfusion Imaging with NExt generation SPECT (REFINE SPECT). J Nucl Cardiol 2018; doi: 10.1007/s12350-018-1326-4. Armstrong AJ, Anand A, Edenbrandt L, Bondesson E, Bjartell A, Widmark A, et al. Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2018; 4: 944-51. Xu J. 200x Low-dose PET Reconstruction using Deep Learning. Computer Science- Computer Vision and Pattern Recognition. Arxiv E-prints; 2017. Mathotaarachchi S, Pascoal TA, Shin M, Benedet AL, Kang MS, Beaudry T, et al. Identifying incipient dementia individuals using machine learning and amyloid imaging. Neurobiol Aging 2017; 59: 80-90.

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The Future of Medical Education Hasan Anıl Atalay

, Lütfi Canat

, Sait Özbir

Department of Urology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract In the present study, new technologies that affect medical education and innovations in the education system are discussed. The contributions of e-learning, simulation, and health information technologies to the education of assistants and medical students in the future have been tried to be explained by providing examples from various research studies. In addition, the future of medical education will be in the field of scientific research, and the importance of patient safety is discussed while adapting to new technologies in medical education. Keywords: Education, medicine, technology

INTRODUCTION The main aim of medical education is to train specialist doctors with full knowledge of modern medicine and who are equipped with the latest knowledge and skills. Modern medicine is currently subdivided into internal medicine, surgery, oncology, pediatrics, and gynecological diseases. Currently, there are many technological developments affecting these areas. There is a consensus worldwide that it is difficult for medical education institutions to succeed with conventional training methods in terms of these rapid technological and social changes (1). While medical education should adapt to this new system, standards should be ensured, and patient safety should not be put at risk.

ORCID IDs of the authors: H.A.A. 0000-0002-2977-1680; L.C. 0000-0001-6481-7907; S.Ö. 0000-0002-9300-6860. Cite this article as: Atalay A, Canat L, Özbir S. The Future of Medical Education. Eur Arch Med Res 2018; 34 (Suppl. 1): S30-S32. Corresponding Author: Hasan Anıl Atalay E-mail: anilatalay@gmail.com Received: 09.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.33043 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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Nowadays, undergraduate and postgraduate medical education is transformed into a model in which students are less associated with patients; this is known as the Halstedian model in the literature, from the volume-based model in which many patients are examined and operated on (2). The reasons for this differentiation in education include development of advanced diagnostic methods, easy access to the doctor, decreased number of complicated surgical procedures, increase in the elderly patient population, and more minimally invasive surgery as surgical treatment (3). Today, surgical simulations rise into prominence in the training of residents because more importance is given to the patient rights, and the number of complicated surgical cases has decreased in our country similar to other countries worldwide. How future doctors are going to be transformed into competent practitioners who can work efficiently and safely in a challenging environment of the health system of the changing world is the challenge faced by everyone working in both undergraduate and graduate medical education. The aim of the present study, which tried to examine the future of medical education, was to determine the rapid evolutionary stages in the future of medicine and to investigate its effects on education. In our study, new imaging and diagnostic methods, minimally invasive surgeries and simulations, and the role of new future technologies in undergraduate and postgraduate medical education are discussed. Technological Innovations in Medical Education Medical simulations reduce the duration of the learning curve of challenging surgical procedures in the work environment without compromising patient safety. The importance of patient safety in our country and in the world is better understood. Therefore, utilizing the learning methods in an environment where skills can be applied and developed before learning in real life is the most ideal (4). Simulation is increasingly used in the education of both medical students and residents.

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Residents can not only apply their clinical skills in a safe environment but also develop their general skills, such as teamwork and leadership (5). Minimally invasive surgery plays an important role in medicine. Therefore, the concept of simulation in surgical training has gained increasing interest. For example, simulation plays a more important role in robot-assisted surgery in resident training. This is because the resident standing by the patient during the robot-assisted surgery cannot fully monitor the skills of the surgeon. However, robotic surgery simulators provide a faster learning of the required skills (6). The three types of simulators used in the medical field are the following: (1) mechanical simulators, (2) simulators that enable to evaluate resident training, and (3) virtual reality (VR). Mechanical simulators are boxes in which the organs are manipulated using surgical instruments, and the organs or objects are placed (dry laboratory training) (7, 8). In the second type, the performance of the residents is assessed by a programmed software of mixed simulators capable of providing feedback, including objects and organs. Simulators with simpler software can measure the duration of the required procedures, the collisions that occur while performing the job, whereas those with more complex software can also evaluate the heat energy and clip placement errors and capture errors. These errors, which are integrated into the simulators, were proposed by experts and were subject to many evaluations by experts before being made available to the residents. VR simulators allow residents and medical students to interact with real-time three-dimensional computer databases. Medical students manipulate computer-generated images and receive feedback on their performance. VR images are generated by the processing of computed tomography or magnetic resonance imaging data. They are not only used in resident training but also used as a preoperative rehearsal of surgery by experienced surgeons. The aim is to minimize the complications that may occur during surgery. In particular, this form of simulation plays an important role in increasing patient safety in the future (9, 10). Training programs should also change in parallel with medical technologies. Since the first successful laparoscopic surgery that was conducted 30 years ago, there has been a revolution in minimally invasive procedures in medicine (11). Recently, robot-assisted surgery has been developed and popular in many surgical branches. The biggest difference between robotic surgery and other conventional surgical procedures is the distance between the surgical site and the surgeon. In laparoscopic or open surgical procedures, while the surgeon is in the operating area, the surgeon in robotic surgery manages the surgery from a distance by a method called tele-surgery. This difference causes surgery to achieve another dimension, and it is foreseen that medical education will change in the future via this groundbreaking change (12). While some of the new practices in medical education are the extension of previous techniques, the majority are recent innovations that require different skills and have a long learning curve. The content of the training, the method of training, and the assessment methods for these various developments should be defined in the future medical curricula. The cost of newer technologies makes it important that educational programs use these expensive resources effectively (13).

Atalay et al. The Future of Medical Education

Video games are seen as one of the alternative training methods for laparoscopic or robotic surgery (14). These games are frequently used for the development of hand, eye, and reflex coordination of residents by providing challenging stimulating environments. Adams et al. (15) investigated the effects of a 6-hour video game in a week on the laparoscopic simulator capabilities of 31 general surgery residents. As a result, it is reported that the assistants had better visual, spatial, and motor coordination. In addition, it was emphasized that the residents should have 6 h of video game experiments a week before the laparoscopic simulator training. Wearable technologies, such as Google GlassÂŽ or augmented reality simulators, are also being tested as a new form of technology that makes medical education more realistic and potentially more effective. In the study conducted by Dickey et al. (16), penile prosthesis surgeries were followed by 10 residents wearing Google GlassÂŽ during the operation, and they were actively asked to participate in the surgery. At the end of the procedures, the contribution of augmented reality to the trainings was investigated by means of a questionnaire. As a result, both faculty members and residents stated that this new technology had a very important contribution to their education. In addition, they reported that augmented reality represented a paradigm shift in surgery, and that this technology would replace other conventional education methods in medical education. In recent years, the latest developments have added new terms, such as artificial intelligence, machine learning, artificial neural networks, and deep learning into our education and training life. It is absolute that future physicians should know these issues. However, there are currently no medical doctor academicians in this field. For this reason, engineers should create new educational projects with software developers and programmers who are experts in these subjects in order for future generations to be familiar with these issues, and these issues should be overcome via multidisciplinary approaches and partnerships. Scientific research is another area of graduate and postgraduate medical education. One of the most important indicators of a quality medical school or clinic is the quality of the residentsâ&#x20AC;&#x2122; thesis and the scientific research studies they make during their education. The Ministry of Health supports high-quality medical research in order to provide new treatments and to improve patient care. In addition to this, it is necessary to create a natural environment for conducting scientific research studies, to find creative subjects, to provide contribution to the medical students on this subject, and to create resources for the necessary financial opportunities. In particular, as in other countries, in-hospital systems can be developed, and the research studies to be supported might be identified by a commission of academicians. Hospital archives should be available to residents and interns with special permissions, and auxiliary staff should be provided to solve problems that might be encountered during the scientific research. The accumulation and storage of data for scientific research is very important. In order for data research, accurate entry, storage, and request of data are neglected in our country. Patient records should be systems that allow the automatic collection of more or less information, including treatment results. The

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accumulation of this information will be used as a resource for the creation of large data in the future and for the establishment of diagnostic or treatment algorithms in cloud systems, such as Azure Microsoft® or Google TensorFlow®. Therefore, the use and guidance of these systems are the subjects of future medical education. In 2014, Peyton et al. (17) investigated the contribution of scientific research to postgraduate education. A total of 256 doctors who were postgraduate students in the United States were reached by mail. The residents were asked to evaluate the impact of scientific studies in their clinics on their education. The majority of the residents stated that attending scientific research studies had a positive effect on their education. In particular, the other important information in the present study is that the medical faculties who are preferred by medical students are the ones who conduct the scientific research studies.

COMMENTS Medicine has come a long way in the past few years. Therefore, medical education and student assessment methods should be adapted to these changes. Training and evaluation are still based on experience gained from clinical practice. Therefore, the education of each student should be personal, and the transition from the volume-based education model (number of assisted cases) to the learning-based system (to do as many as one can learn) should gain importance. Medical simulation and, especially, VR will play a major role in the future of medical education. Telemonitoring and wearable technologies (e.g., Google Glass®) will be in the curriculum of future education programs. The development of learning technologies, e-learning, social media, and mobile devices and applications will become more noticeable in daily practice (18). The importance of evidence-based medicine is increasing. Therefore, it is thought that the importance given to the duration of scientific research in medical education will gain more value.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - H.A.A.; Design - H.A.A.; Supervision - L.C.; Data Collection and/or Processing - S.Ö.; Analysis and/or Interpretation - L.C.; Literature Search - S.Ö.; Writing Manuscript - H.A.A.; Critical Review - L.C. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

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Issenberg SB, McGaghie WC. Looking to the future. In: McGaghie WC, ed. International Best Practices for Evaluation in the Health Professions. London, UK: Radcliffe Publishing Ltd.; 2013: 341-59. 2. Nguyen L, Brunicardi FC, Dibardino DJ, Scott BG, Awad SS, Bush RL, Brandt ML. Education of the modern surgical resident: Novel approaches to learning in the era of the 80-hour workweek. World J Surg 2006; 30: 1120-7. 3. Chikwe J, de Souza AC, Pepper JR. No time to train the surgeons. BMJ 2004; 328: 418-9. 4. Ahmed K, Jawad M, Dasgupta P, Darzi A, Athanasiou T, Shamim A. Assessment and maintenance of competence in urology. Nat Rev Urol 2010; 7 :403-13. 5. Aggarwal R, Mytton OT, Derbrew M, Hananel D, Heydenburg M, Issenberg B, et al. Training and simulation for patient safety. Qual Saf Health Care 2010;19 Suppl 2: i34-43. 6. Thiel DD, Lannen A, Richie E, Gajarawala NM, Igel TC. Simulation-based training for bedside assistants can benefit experienced robotic prostatectomy teams. J Endourol 2013; 27: 230-7. 7. Samia H, Khan S, Lawrence J, Delaney CP. Simulation and its role in training. Clin Colon Rectal Surg 2013; 26: 47-55. 8. King N, Kunac A, Merchant AM. A Review of Endoscopic Simulation: Current Evidence on Simulators and Curricula. J Surg Educ 2016; 73: 12-23. 9. Yiannakopoulou E, Nikiteas N, Perrea D, Tsigris C. Virtual reality simulators and training in laparoscopic surgery. Int J Surg 2015; 13: 60-4. 10. Moglia A, Ferrari V, Morelli L, Ferrari M, Mosca F, Cuschieri A. A Systematic Review of Virtual Reality Simulators for Robot-assisted Surgery. Eur Urol 2016; 69: 1065-80. 11. Clayman RV, Kavoussi LR, Figenshau RS, Chandhoke PS, Albala DM. Laparoscopic nephrectomy: initial case report. J Urol 1991; 146: 27882. 12. Marini CP, Ritter G, Sharma C, McNelis J, Goldberg M, Barrera R. The effect of robotic telerounding in the surgical intensive care units impact on medical education. J Robot Surg 2015; 9: 51-6. 13. Subramonian K, Muir G. The ‘learning curve’ in surgery: what is it, how do we measure it and can we influence it? BJU Int 2004; 93: 1173-4. 14. Lynch J, Aughwane P, Hammond TM. Video games and surgical ability: a literature review. J Surg Educ 2010; 67: 184-9. 15. Adams BJ, Margaron F, Kaplan BJ. Comparing video games and laparoscopic simulators in the development of laparoscopic skills in surgical residents. J Surg Educ 2012; 69: 714-7. 16. Dickey RM, Srikishen N, Lipshultz LI, Spiess PE, Carrion RE, Hakky TS. Augmented reality assisted surgery: a urologic training tool. Asian J Androl 2016; 18: 732-4. 17. Peyton CC, Badlani GH. Dedicated research time in urology residency: current status. Urology 2014; 83: 719-24. 18. Katz MS. Social media and medical professionalism: the need for guidance. Eur Urol 2014; 66: 633-4.

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Impact of Technological Advancements in Otolaryngology Berk Gürpınar

, Ayça Başkadem Yılmazer

, Yavuz Uyar

Department of Otolaryngology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Otolaryngology mainly deals with the organs that are located inside the body and bony compartments. This makes the diagnosis and treatment complicated to some extent. Inventions and advancements in new devices help doctors to identify and cure the diseases rapidly and effectively. In addition, target-specific therapies prevent nearby structures from the adverse effects of the treatment. The aim of this review was to search the database and to limit our search for the last 10year period. New devices are emerging daily, and some new inventions might be overlooked. The most commonly used ones or interestingly efficient inventions that relieve the need for surgery are considered. Furthermore, the most commonly used multidisciplinary devices are thought to be beyond the scope of this review. In addition to otological genetic treatments, genetic advancements are not mentioned. For easy reading, topics have been further divided into subsections of otolaryngology as well as chronologically classified. Unfortunately, the database provided no support for the overall use or beneficial studies about those below-mentioned devices. Keywords: Technology, otolaryngology, device

INTRODUCTION ORCID IDs of the authors: B.G. 0000-0002-6060-0791; A.B.Y. 0000-0001-9967-8046; Y.U. 0000-0001-8732-4208. Cite this article as: Gürpınar B, Başkadem Yılmazer A, Uyar Y. Impact of Technological Advancements in Otolaryngology. Eur Arch Med Res 2018; 34 (Suppl. 1): S33-S36. Corresponding Author: Berk Gürpınar E-mail: b_gurpinar@yahoo.com Received: 22.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.36855 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Scientific developments help in healing the diseases more rapidly, not just because of the evolution of new methods and techniques but also the development and invention of new medical devices. Unfortunately, the invention and demand cycles for new devices are cumbersome; most of these new state-of-the-art pieces may be proven not to be so useful or cost-effective, whereas others are being introduced in an inevitable manner. The aim of this review was to search various databases and the internet website of the Food and Drug Administration (FDA) for new achievements. However, there were uncountable gadgets, so the search was systematically limited within the last 10-year period and did not include instruments that are shared with other branches. The genetic investigations are thought to be beyond the scope of this review. In addition, nanotechnological or chemical achievements will be discussed in other studies. The achievements are classified and divided into relevant topics for convenience and easy reading. Otology Microtia and aural atresia are congenital malformations of the ear. The results of total reconstructions of the ear with autogenous costal cartilage cannot always be satisfactory due to a lack of the shape and definition of a normal ear. Three-dimensional print technology mimics the unaffected ear to build up a new auricle composed of polylactic acid compatible with the body as an implant (1, 2). Eustachian tube dysfunction (ETD) is one of the important causes of conductive hearing loss. Since therapeutic methods have been insufficient to treat ETD, a balloon catheter is placed into the cartilage portion of the eustachian tube, and dilation is provided via inflation of the balloon. The results of the Eustachian tube dilation procedure are curable in both clinical and laboratory in the long-term (3, 4).

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Cochlear implant (CI), also referred to as “bionic ear,” is being used in humans since 1972. Bilateral CI use appears to have benefits on spoken language, comprehension and expression, sound localization, and fever distortion in speech production. If there is any defect in patency and integrity of the cochlea or related neural structures, CI is not feasible, but auditory brainstem implantation (ABI) is another option that is placed directly to the brainstem close to eight nerve nuclei bypassing the cochlea and cochlear nerve. Especially for patients with post-lingual hearing loss, ABI provides good support in combination with lip reading (5-8). In case of sensorineural hearing loss due to inner ear anomalies, hearing aids, CI, or ABI is mainly supportive. Therefore, biological interventions are needed for the protection, repair, and regeneration of the inner ear. Gene transfer technology (GTT) is currently promising to provide a cure in genetic anomalies of the inner ear. In GTT, the main approaches for gene delivery are systemic, transtympanic, and cochlear. The gene therapy reagents include viral vectors, siRNA, and small particles. Auditory nerve preservation and fiber regeneration, hairy cell (HC) preservation, and HC regeneration have been performed experimentally on animals yet via biologically relevant genes (9). In addition to the hearing functions of the ear, balancing system defects are also in the scope of improving technology. Bilateral vestibular dysfunction affects the quality of life negatively; recently, vestibular implants are performed in some cases, but not routinely. The device with three leads is placed on the postauricular area. The leads are inserted into the perilymphatic space adjacent to the membranous labyrinth of each semicircular canal (10). To our knowledge, there are few cases in the literature, so the long-term results remain unknown. Special glasses (SEETROËN®) are invented that help to prevent motion sickness. They have a blue liquid that can flow in front of and around the eyes. The liquid stays horizontal with the ground, regardless of how the vehicle moves, and so provides a sort of stability to the eyes and a reference point for the brain (11). A new achievement in the field of tympanostomy tube insertion is SOLO TTD®, a small handheld device with the ear tube pre-

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loaded at the tip. Ear surgeons have everything they need for ear tube surgery in this one device. It performs the tympanostomy and without holding back the surgeon’s hand, inserts the tympanostomy tube itself. Rhinology Chronic sinusitis may often require repeat surgeries; those secondary interventions are more dangerous because of the altered anatomy of the sinuses. Thus, navigation systems are being used and developed. Medtronic® launched its StealthStation ENT surgical navigation system that works by generating an electromagnetic field around the target patients’ anatomy during surgery so instrument positioning can be dynamically tracked. Intersect ENT is a releasing SINUVA® sinus implant for treating nasal polyp disease in adults who underwent previous surgical sinus procedures. The device elutes mometasone furoate for 90 days to reduce inflammation directly at the polyps. Patients receiving SINUVA experienced a statistically significant reduction in bilateral polyp grade (p=0.007), corresponding to 74% relative reduction in the extent of ethmoid polyp disease compared with controls (12). STS Medical® has launched a sinus stent, indicated for the treatment of chronic sinusitis, as part of functional endoscopic sinus surgery to help keep the sinus cavity open post-surgery. It can also be used to address nose job failures, chronic allergic rhinitis, and as an option over sinuplasty. The device is flexible and designed to anchor in place and not move around. It is then left within the lumen for up to 4 weeks, allowing the surrounding tissue to heal. Removal of the device is an in-office procedure that does not require anesthesia. Spirox® developed an absorbable nasal implant designed to support the nasal cartilage and prevent nasal valve collapse, which can contribute to nasal obstruction. No adverse changes in cosmetic appearance have been reported. Head and Neck Surgery A new technology is introduced to spot the nerves within the tissue during surgeries optically (13). The technology uses collimated polarized light imaging, and by rotating the polarization, one can spot the nerve tissue (Figure 1). SnooZeal® is a new snoring prevention device. It places electrodes above and below the tongue, stimulates the tongue to give it a workout, trains the tongue muscle, and helps to keep it at least partially contracted even at night and keep it from completely relaxing and collapsing during the night (Figure 2) (14).

Figure 1. Collimated polarized light imaging helps to spot the nerve tissue. (A) Green arrow shows the nerve, but when polarization is changed, it is not seen in (B). Blue arrow shows the opposite

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Inspire Medical Systems® has received FDA approval. Upper airway stimulation is used as an option for patients who are poor candidates for continuous positive airway pressure. The system includes a neurostimulator to which two leads are connected. One runs to the chest in order to continue to sense the person’s breathing state, and the other lead is used to stimulate airway muscles to open up the passageway in concert with the lungs. The procedure does not alter the patient’s airway anatomy, and the device can be turned on and off and reprogramed as needed. Another neurostimulator to treat sleep apnea is the aura 6000® system. It includes an implantable neurostimulator with elec-

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trode leads going to the hypoglossal nerve that controls the movement of the tongue. Patients can turn the device on and off using a paired remote control, as well as wirelessly recharge it as necessary. It acts like a pacemaker for the tongue, cycling through stimulating different muscles of the organ to open the upper airway during sleep. Researchers at the Universidad Politécnica de Madrid and Universidad Autónoma de Madrid have designed a tracheostomy device that identifies the trachea, makes an incision for an alternative airway, dilates the new airway, and maintains the airway

Gürpınar et al. Impact of Technological Advancements in Otolaryngology

by electrical and pneumatic means. Researchers aim to someday have the device be as commonplace and easy to use as automatic external defibrillators. Cook Medical® launched a new set of access products for performing sialoendoscopies or removal of salivary stones and other obstructions within the salivary duct. A soft-tipped wire is used to introduce dilators that expand the duct and allow for placement of a sheath through which extractors can be introduced and manipulated safely to remove salivary stones. Olympus® has released a new disposable tonsil adenoid debrider by combining monopolar energy with a malleable shaver blade. It allows the surgeon to cut and coagulate with a single device, reducing the need to exchange instruments. In addition, distal suction allows the shaver blade to be used as a suction device for blood and fluid, leading to better visualization of the surgical site. Researchers from Stanford have developed a new smartphone-based diagnostic device to enable earlier diagnosis of oral lesions. OScan® creates detailed images of the oral cavity and screens the mouths for suspicious oral lesions. It contains two rows of fluorescent light-emitting diodes that illuminate the mouth and highlight lesions and dark spots (Figure 3).

Figure 2. Electrodes stimulate the tongue above and below to train the muscles in order to prevent sleep apnea and snoring

Laryngology PEG30®, a new type of synthetic polymer that mimics the viscoelastic properties of human vocal cords, was shown to restore vibration to the vocal folds that have become stiff and unable to vibrate due to scarring. It has been shown to be safe in many FDA-approved drugs and medical devices, so researchers are hoping to use the modified polymer as an “injectable device” that is applied directly into the vocal folds every 6 months (15). Artificial Larynx is on its way; the Palatometer® is capable of reading how one’s tongue contacts the palate during speech. To use the device, a person puts the palatometer inside the mouth and mouths words normally. It tries to translate those mouth

Figure 3. OScan® contains two rows of fluorescent lightemitting diodes that illuminate the mouth and highlight lesions and dark spots

Figure 4. Non-invasive anti-reflux device

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movements into words before reproducing them on a small sound synthesizer.

EndoGastric Solutions launched the EsophyX® Z+ device designed for use in transoral incisionless fundoplication procedures to reconstruct the gastroesophageal valve to treat patients with severe gastroesophageal reflux disease.

A noninvasive anti-reflux device is introduced by Somna Therapeutics®. This wearable device is placed over the neck only at nighttime and is believed to compensate for the relaxing effect of the upper esophageal sphincter (Figure 4).

CONCLUSION As of today, technology helps in the diagnosis and treatment of many diseases that were deemed to be “impossible to reach to treat or unable to treat.” In addition, the new inventions introduce new diseases that were unknown many years ago. The state-of-the-art development in the medical field should address the prevention of the diseases. Many researchers are trying to find the cause of the diseases before they erupt. For now, new terms, such as “minimally invasive” or “delicate surgery,” are brought into the vocabulary of surgical interventions, just because of new devices. It is a well-known fact that highly advanced technological devices can reach, see, identify, or remove the disease far better than human capabilities. Nevertheless, to our belief, human common sense should be the last decision factor in all of those aforementioned steps.

Peer-review: Externally peer-reviewed.

9. 10.

11.

12. 13.

Author Contributions: Concept - B.G.; Design - B.G., Y.U.; Literature Search - A.B.Y.; Writing Manuscript - B.G.; Critical Review - A.B.Y. Conflict of Interest: The authors have no conflicts of interest to declare.

14.

Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1.

Zeng W, Lin F, Shi T, Zhang R, Nian Y, Ruan J, et al. Fused deposition modelling of an auricle framework for microtia reconstruction based on CT images.

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15.

Witek L, Khouri KS, Coelho PG, Flores RL. Patient-specific 3D Models for Autogenous Ear Reconstruction. Plast Reconstr Surg Glob Open 2016; 4: e1093. Gürtler N, Husner A, Flurin H. Balloon Dilation of the Eustachian Tube: Early Outcome Analysis. Otol Neurotol 2015; 36: 437-43. Ockermann T, Reineke U, Upile T, Ebmeyer J, Sudhoff HH. Balloon Dilatation Eustachian Tuboplasty: A Clinical Study. Laryngoscope 2010; 120: 1411-6. Medina M, Di Lella F, Di Trapani G, Prasad SC, Bacciu A, Aristegui M, et al. Cochlear Implantation Versus Auditory Brainstem Implantation in Bilateral Total Deafness After Head Trauma: Personal Experience and Review of the Literature. Otol Neurotol 2014; 35: 260-70. Hainarosie M, Zainea V, Hainarosie R. The evolution of cochlear implant technology and its clinical relevance. J Med Life 2014; 7: 1-4. Lammers MJ, van der Heijden GJ, Pourier VE, Grolman W. Bilateral cochlear implantation in children: a systematic review and best-evidence synthesis. Laryngoscope 2014; 124: 1694-9. Sanna M, Di Lella F, Guida M, Merkus P. Auditory Brainstem Implants in NF2 Patients: Results and Review of the Literature. Otol Neurotol 2012; 33: 154-64. Fukui H, Raphael Y. Gene therapy for the inner ear. Hear Res 2013; 297: 99-105. Phillips JO, Ling L, Nie K, Jameyson E, Phillips CM, Nowack AL, et al. Vestibular implantation and longitudinal electrical stimulation of the semicircular canal afferents in human subjects. J Neurophysiol 2015; 113: 3866-92. Bridgeman B, Blaesi S, Campusano R. Optical correction reduces simulator sickness in a driving environment. Hum Factors 2014; 56: 1472-81. SINUVA Prescribing Information, Intersect ENT. December 2017. Chin KWTK, Engelsman AF, Chin PTK, Meijer SL, Strackee SD, Oostra RJ, et al. Evaluation of collimated polarized light imaging for real-time intraoperative selective nerve identification in the human hand. Biomed Opt Express 2017; 9: 4122-34. Dong Y, Zhao M, Su M, Ding N, Zhang X. Efficacies of stimulation of genioglossus in mild-to-moderate obstructive sleep apnea syndrome patients after uvulopalatopharyngoplasty. Zhonghua Yi Xue Za Zhi 2014; 94: 1726-8. Karajanagi SS1, Lopez-Guerra G, Park H, Kobler JB, Galindo M, Aanestad J, et al. Assessment of Canine Vocal Fold Function after Injection of a New Biomaterial Designed to Treat Phonatory Mucosal Scarring. Ann Otol Rhinol Laryngol 2011; 120: 175-84.

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Optical Coherence Tomography Angiography: A New Vision Into The Future of Retinal Imaging Burak Erden Department of Ophthalmology, University of Health Sciences, OkmeydanÄą Education and Research Hospital, Ä°stanbul, Turkey

Abstract Optical coherence tomography angiography (OCTA) is a brand new imaging tool developed and clinically introduced recently into the ophthalmological diagnostic tool armamentarium. OCTA enables a segmented and detailed examination of retinal vasculature and structure in a non-invasive fashion within a few seconds based on the present and widespread OCT technology. Retinal and glaucoma specialists can evaluate vascular circulation in every possible separate layer for the first time in ocular imagining history and acquire a new understanding in the pathological process of ophthalmological diseases using OCTA. The developing process of this innovative technology is still in progress by companies based on the clinical feedback of the leading clinicians, in software and hardware, overcoming the technical limitations of OCTA and leading to re-evaluation of wellknown diseases. Keywords: Optical coherence tomography angiography, retina, glaucoma

INTRODUCTION

ORCID ID of the author: B.E. 0000-0003-0650-4552. Cite this article as: Erden B. Optical Coherence Tomography Angiography: A New Vision Into The Future of Retinal Imaging. Eur Arch Med Res 2018; 34 (Suppl. 1): S37-S41. Corresponding Author: Burak Erden E-mail: drburakerden@gmail.com Received: : 01.10.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.40427 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

There are several milestones in ophthalmological imaging that contributed to the clinical understanding and treatment approaches of retinal diseases. First, in the 1960s, fundus fluorescein (FFA) (1) and indocyanine green angiography (2) were introduced based on the optical fluorescence characteristics of intravenous dyes, widening our knowledge about choroidal and retinal circulation and vascular pathologies. In the 2000s, optical coherence tomography (OCT) appeared into our daily practice, enlightening the microstructure of both retina and choroid in microns, enabling clinicians and researchers to understand the pathogenesis of daily encountered diseases, and leading to a much superior clinical approach. Recently, another milestone in imaging, optical coherence tomography angiography (OCTA), is developed based on the principles of conventional OCT. Now, for the first time in ophthalmological history, we can demonstrate the retinal microcirculation in segmented fashion. The non-invasive OCTA enabled the separate evaluation of the superficial and deep capillary plexi of the retina, choroid, and peripapillary circulation. Even mysterious vascular lesions hidden under the retina pigment epithelium (RPE) can be detected and evaluated. Although this brand new tool may have been underestimated by some retinal specialists, especially due to the technical limitations, at the beginning, its fast progress, with the feedback between the leading clinicians and companies, led to perfection. The many publications in the literature in several subspecialties of ophthalmology, such as glaucoma, cornea, or retina alone, indicated that OCTA has already become a must of our imaging armamentarium. Technical Features Optical coherence tomography angiography (OCTA) is technically derived from the conventional OCT technology. It compares the decorrelation signal (differences in the backscattered OCT signal intensity or amplitude) between sequential OCT B-scans obtained precisely at the same cross-section of the retina to construct a three-dimensional map of blood flow. This technique

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may be comparable with subtraction of two consecutive images to represent motional differences (Figure 1). The sites of signal differences between sequential OCT high-resolution B-scans represent automatically and only erythrocyte movements in the retinal vessels, leading to an angiographical image in a non-invasive fashion (Figure 2). The OCTA required naturally higher scanning speeds (70 kHz vs. 25 kHz) and faster eye trackers than conventional OCT systems in order to obtain signal differences at precisely the same retinal loci without increasing the scanning time. Several medical imaging companies released different models into the market (Figure 3) and are still developing software and hardware systems in cooperation with the clinicians on the retinal field to solve the real-life conflicts of their systems. Recently, although AngioPlex (Carl Zeiss Meditec, Dublin, CA, USA) is also widely evaluated in many publications, the AngioVue OCTA (Optovue, Inc., Fremont, CA, USA) has a minor superiority in aspects of clinical usefulness over the other companies. Comparison of OCTA with Conventional FFA In contrast to OCTA, conventional FFA examination is basically an invasive test requiring intravenous administration of fluorescein dye and a time-consuming practice, depending on the clin-

Figure 1. The basic principle of OCTA. Imaging of motion differences of two consecutive photo images digitally reproduces the image of water flow from a tap

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ical situation, up to 10 min. With FFA, clinicians can evaluate the functional status and integrity of the microvascular structure of the retina, choroid, and even RPE based on the specific patterns of fluorescein, such as leakage, pooling, or staining. However, this two-dimensional FFA angiogram lacks the capacity of differentiation of over- or underlying tissues, making the exact imaging of, for example, type 2 choroidal neovascular membranes (CNVs) under RPE impossible, which were ill-defined by FFA and had been called as “occult membranes.” These blurred borders of type 2 CNVs complicated the photodynamic therapy, which was the only treatment option in wet age-related macular degeneration (AMD) one decade ago. Nowadays, through OCTA, we can analyze the “occult membranes” in details and evaluate even the maturity of these CNVs. In contrast to conventional FFA, OCTA is non-invasive, captured in seconds, and three-dimensional. These three-dimensional images enable retinal specialists to evaluate each vascular layer separately. The only inferiority of OCTA is its lack of information about vascular integrity and function (Table 1). Clinical Applications of OCTA Diabetic retinopathy (DRP) can be defined as a microvascular disease, developed secondary to chronic hyperglycemia, based mainly on capillary and microcirculation changes of the retina. Ischemia and non-perfusion areas are crucial to determine the degree and status of the disease (3). With conventional FFA, non-perfusion and leakage areas can be detected, unless images are obscured by superposing of the capillary plexi (4). In many cases, chronic capillary leakage in the late phases of the conventional angiograms superposes the critical foveal avascular zone (FAZ) or peripheral non-perfusion areas so that the clinicians cannot determine the status of the macula or periphery reliably. Through OCTA, superficial and deep capillary plexi can be evaluated by automated segmentation separately so that FAZ enlargement secondary to macular ischemia can be detected in deep or superficial plexus (5), pointing out to worse prognosis at even the early non-proliferative DRP stages. Lately, the major disadvantage of lacking wide-field imaging in OCTA has been overcome by various montage techniques in recent software versions so that real peripheral capillary dropout areas can be determined without the FFA superposing leakage effect (6); clinicians can determine for proper treatment mo-

Figure 2. The signal differences between two sequential structural B-scans reveal vascular structure based on intravascular erythrocyte movements

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Erden B. Optical Coherence Tomography Angiography

Figure 3. Comparison of technical features of leading ophthalmological imaging companies' OCTA systems. From left to right: Zeiss, Optovue, Heidelberg, Topcon, Nidek, and Canon dalities according to these new findings. In patient follow-up, the progression or regression of foveal or peripheral ischemia, capillary dropout in deep or superficial plexi, can be also easily visualized. In neovascular wet AMD, three different subtypes of CNV were defined; type 1 is underlying beneath the RPE, type 2 CNVs are of classic nature, originating from the choroid branching into the retina, and type 3 CNVs are called as retinal angiomatous proliferations, whereas these lesions are mainly developing in the retinal layers. OCTA can detect all these three subgroups of choroidal neovascular membranes, mapping them in different colors to differentiate these lesions from normal retinal capillary plexi. This ability of visualization enables us to isolate, define, understand, and follow the treatment re-

sponse of CNVs (Figure 4). Recently, the degree of maturity of CNVs was described in various publications, changing our anti-vascular endothelial growth factor (VEGF) treatment indications in a proactive fashion (7). In contrast to structural OCT scans, where the retinal specialists search for disease activation in the form of intra- or subretinal fluid, the immaturity of CNVs might be a new indication for anti-VEGF treatment, preventing the patientsâ&#x20AC;&#x2122; visual impairment in a proactive fashion. OCTA can detect even polypoidal choroidal vasculopathy lesions (8), underneath the highly reflective RPE, and their treatment response in a reliable degree (9). Another often conventional OCT scans mysterious lesions are pigment epithelial detachments (PEDs) of different types. Owing to the high reflectivity of RPE, PEDs are different to classify, and recently combined with en face OCT scans OCT angiograms, clinicians

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Figure 4. A type 2 CNV detected at the outer retina beneath the RPE (left) regresses after anti-VEGF treatment (middle) and reactivates in follow-up (right) as demonstrated by AngioVue follow-up modus Table 1. The faster acquisition time, its’ non-invasive nature and ability of segmentation are dominant advantages of OCTA, whereas FFA is still crucial to obtain information about the integrity and function of retinal vasculature FFA

OCTA

10-15 min

3sec

Need of Dye

Artefacts

Functional

Structural

-/+

Segmentation Duration

Information Wide-field

can evaluate the critical component of PEDs, namely vascularization (10). In chronic central serous chorioretinopathy cases, there was an ongoing debate about the treatment options. The most commonly suspected etiology for chronicity of this disease was a possible CNV, which was shown also by OCTA angiograms (11), thus indicating the anti-VEGF treatment for such chronic recurrent cases. In the area of glaucoma, a progressive disease, where glaucoma specialists relied on visual field examinations and retinal nerve fiber analyses with structural OCT for detection of progression, OCTA enlighten the subtle peripapillary vascular changes prior to any clinical or imaging findings (12). Kumar et al. found that the glaucoma severity score in OCTA identifies preperimetric glaucoma and early glaucoma better than visual fields (13). Averaging the decorrelation signal in OCT angiograms allows us to calculate the flow index of the optic

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disc area, which is lower in glaucomatous eyes (14) than in the normal population (15).

CONCLUSION The introduction of OCTA into our daily practice has changed our understanding and clinical approach in certain diseases dramatically. This new technologies’ ability of further progress is welcomed by the ophthalmological society, even in each subspecialty. The cooperation and co-work of companies with clinicians is producing new astonishing results ready to change and widen our vision into ophthalmic diseases greatly in the coming years. OCTA itself has already become a must in our daily diagnostic technological armamentarium.

REFERENCES 1. 2.

Novotny HR, Alvis DL. A method of photographing fluorescence in circulating blood in the human retina. Circulation 1961; 24: 82-6. Yannuzzi LA, Slakter JS, Sorenson JA, Guyer DR, Orlock DA. Digital indocyanine green videoangiography and choroidal neovascularization. Retina 1992; 12: 191-223. Arend O, Wolf S, Jung F, Bertram B, Pöstgens H, Toonen H, et al. Retinal microcirculation in patients with diabetes mellitus: dynamic and morphological analysis of perifoveal capillary network. Br J Ophthalmol 1991; 75: 514-8. Mendis KR, Balaratnasingam C, Yu P, Barry CJ, McAllister IL, Cringle SJ, et al. Correlation of histologic and clinical images to determine

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the diagnostic value of fluorescein angiography for studying retinal capillary detail. Invest Ophthalmol Vis Sci 2010; 51: 5864-9. 5. Couturier A, Mané V, Bonnin S, Erginay A, Massin P, Gaudric A, et al. Capillary Plexus Anomalies in Diabetic Retinopathy on Optic Coherence Tomogaphy Angiography. Retina 2015; 35: 2384-91. 6. Or C, Sabrosa AS, Sorour O, Arya M, Waheed N. Use of OCTA, FA, and Ultra-Widefield Imaging in Quantifying Retinal Ischemia: A Review. Asia Pac J Ophthalmol (Phila)2018; 7: 46-51. 7. Miere A, Butori P, Cohen SY, Semoun O, Capuano V, Jung C, et al. Vascular Remodeling of Choroidal Neovascularization After anti-Vascular Endothelial Growth Factor Therapy Visualized on Optical Coherence Tomography. Retina 2017; DOI: 10.1097/ IAE.0000000000001964. 8. de Carlo TE, Kokame GT, Kaneko KN, Lian R, Lai JC, Wee R. Sensitivity and Specificity of Detecting Polypoidal choroidal Vasculopathy With En Face Optical Coherence Tomography and Optical Coherence Tomography Angiography. Retina 2018; DOI: 10.1097/ IAE.0000000000002139. 9. Eriş E, Perente İ, Vural E, Yaşa D, Ozkaya A. Assessment of focal laser photocoagulations’ early effect on polypoidal choroidal vasculopathy with optical coherence tomography angiography. Lasers Med Sci 2018; DOI: 10.1007/s10103-018-2463-3.

Erden B. Optical Coherence Tomography Angiography

10. Tan ACS, Freund KB, Balaratnasingam C, Simhaee D, Yannuzzi LA. Imaging of Pigment Epithelial Detachments with Optical cohernece Tomography Angiography. Retina 2018; 38: 1759-69. 11. Moussa M, Leila M, Khalid H, Lolah M. Detection of Silent Type I Choroidal Neovascular Membrane in Chronic Central Serous Chorioretinopathy Using En Face Swept-Source Optical Coherence Tomography Angiography. J Ophthalmol 2017; DOI: 10.1155/2017/6913980. 12. Lee EJ, Lee KM, Lee SH, Kim TW. OCT Angiography of the Peripapillary Retina in Primary Open-Angle Glaucoma. Invest Ophthalmol Vis Sci 2016; 57: 6265-70. 13. Kumar RS, Anegondi N, Chandapura RS, Sudhakaran S, Kadambi SV, Rao HL, et al. Discriminant Function of Optical Coherence Tomography Angiography to Determine Disease Severity in Glaucoma. Invest Ophthalmol Vis Sci 2016; 57: 6079-88. 14. Jia Y, Wei E, Wang X, Zhang X, Morrison JC, Parikh M, Lombardi LH, et al. Optical coherence tomography angiography of optic disc perfusion in glaucoma. Ophthalmology 2014; 121: 1322-32. 15. Jia Y, Morrison JC, Tokayer J, Tan O, Lombardi L, Baumann B, et al. Quantitative OCT angiography of optic nerve head blood flow. Biomed Opt Express 2012; 3: 3127-37.

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We are Being Introduced to New Developments on the Imaging Field Day by Day Serkan Arıbal

, Hakan Önder

, Recep Yılmaz Bayraktarlı

Department of Radiology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract New developments are rapidly ongoing in the field of radiology. In this way, the interventional procedures can be performed more easily by using both imaging and images. Nowadays, 7 T magnetic resonance imaging (MRI) has been developed, and we are beginning to see the results. We started to use artificial intelligence in the field of radiology, and it appears to facilitate our job. Prostate cancer can be easily diagnosed and treated using multiparametric MRI. Keywords: 7 T MRI, artificial intelligence, multiparametric MRI

ORCID IDs of the authors: S.A. 0000-0002-0338-2652; H.Ö. 0000-0001-5207-3314; R.Y.B. 0000-0001-6980-649X Cite this article as: Arıbal S, Önder H, Yılmaz Bayraktarlı R. We are Being Introduced to New Developments on the Imaging Field Day by Day. Eur Arch Med Res 2018; 34 (Suppl. 1): S42-S45. Corresponding Author: Hakan Önder E-mail: drhakanonder@hotmail.com Received: 03.10.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.75046 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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The first 7 T magnetic resonance imaging (MRI) scanner for diagnostic imaging is designed by the medical industry for unprecedented breakthroughs in clinical care. The unique dual mode allows you to switch between clinical and research operations, with separate databases to distinguish between clinical and research scans. This advanced ultra-high field technology has the potential to keep you at the cutting edge of MRI, attract the brightest minds to your facility, sharpen your competitive edge, and strengthen your reputation. It unlocks your potential to publish new insights first and set the pace in diagnostic imaging (Figure 1. a-h.). Discovering new ground in MRI can help you significantly enhance clinical knowledge. Imaging at 7 T offers more than double the SNR of 3 T to support higher resolution for greater detail. This is the first-ever 7 T MRI scanner that produces cross-sectional images of the head and knee for diagnostic imaging intended for patients >66 lbs (1, 2). Welcome to a whole new world in MRI. Artificial Intelligence in Radiology Practice Who would say that there would be no need for doctors in the future? With the advancing technology, more and more machines have been used in the field of health sciences, and we hear these types of questions more often since artificial intelligence (AI) is becoming more familiar and popular in our lives. Surely, radiologists are not the only, or even the first, professionals to have their specialty modified by AI. Other areas of medicine have also been thus affected (3). Artificial intelligence is a smart behavior performed by devices, which is called as intelligence when done by humans. The purpose of AI is to imitate the intelligence of a human, in this sense, to gain the ability of learning to the computers (4). In historical development, the primary method for this system is computer-assisted diagnosis system that allows detecting a certain lesion or probable pathological area in order to advise the radiologist for the lesion rather than to identify a specific diagnosis, whereas new methods of AI aim to present a specific diagnosis using the existing data pool. Expert Systems (ES), Fuzzy Logic (FL), Artificial Neural Networks (ANN), and Genetic Algorithms (GA) are the main topics of AI. ES are a kind of computer-generated consultation system based on areas of expertise and have the steps of description, conceptualization, formulation, testing,

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ArÄąbal et al. New Developments on Radiology Field

collect information about the samples, make generalizations, and then make a decision when encountering the examples never seen by using the information learned (7). GA are the intuitive methods that can be used in cases that cannot be solved by traditional solution techniques or problems that are difficult to solve (Figure 2) (8). The impact of AI on the routine of the radiologist will probably occur gradually. The main contribution of the radiologist is not simply to provide this information but to integrate it with the clinical data, contributing in a more holistic way to the diagnosis and individualized treatment of the patient. The ones who adapt and use these technological tools and systems would have advantages over those who resist it. In addition, radiologists who have not adapted to the changes and have not learned the new techniques have more difficulty in the current job market (3, 9). Brief Overview of Multiparametric MRI and MR-Guided Fusion Biopsy of Prostate Cancer Multiparametric MRI (mp-MRI), which has become available in recent years, is used to inform about the prostate tissue, detecting prostate cancer, its localization, and spread (10-12). The high-resolution T2A sequences found in mp-MRI are used to evaluate the anatomy and tumor localization of the prostate, diffusion-weighted imaging and MR spectroscopy are used to characterize the lesion, and contrast enhancement of the lesion is evaluated by dynamic contrast-enhanced sequences, thus achieving high sensitivity in the detection of cancer (13-15). Prostate biopsy is applied to men who have a high level of serum prostate-specific antigen (PSA) and/or who have suspected cancer in rectal finger examination. Transrectal ultrasound (TRUS)-guided systematic 12-core biopsy is still widely used and is the first method of choice due to its short application time, lower costs, being easier to learn and, not requiring special equipment. Additionally, the equipment is reusable. MR-assisted prostate biopsies are more frequently used in patients with persistently high PSA, with suspected lesion in MRI, whose first biopsies were negative, or where biopsy was not applied before, and in cases with biochemical recurrence after active observation and radiotherapy. It is reported that the rate of detecting cancer in randomized biopsies is 22%-29%, whereas it is 38%-59% in transrectal MR-guided biopsies with applied 1.5 T MR. The different methods in prostate biopsies with MRI are as follows:

Figure 1. a-h. Clear identification of anatomical structures with increased tissue contrast and high resolution at 7T (a-d); Fine structure visible in the lesion with different contrasis (e-h) and evaluation, respectively (5). The main difference between FL and ES is the addition of experience as well as knowledge to all stages in FL. In other words, experiences are used effectively in FL. Owing to this feature, FL is an algorithm that considers the flexible and variable structure of human thought (6). ANN

1. Cognitive Fusion Biopsy: It is a method where US-guided standard TRUS biopsy is applied in another location to the lesion that is detected by MRI. 2. Direct MR-Guided Biopsy (In-Bore): After a suspected area in mp-MRI is signed with a needle, a sample is obtained again with MRI in MR. MRI-guided biopsy takes a long time and is expensive. However, it is seen that MRI-guided biopsies are 20% more effective than TRUS in detecting clinically important prostate cancer. 3. MRI/TRUS Fusion Biopsy: The images obtained by mp-MRI are integrated into the biopsy device to form fused images, and the location of cancer in the prostate is marked three

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Figure 2. A basic example of an artificial intelligence desing in problem solving and diagnosis dimensional. During the procedure, the points, where the biopsy will be performed by motion and angle sensors with a semi-robotic arm, are determined, and the biopsy is performed directly from the identified areas. Thus, the biopsies will be more targeted, and less number of them needs to be obtained. For this purpose, Philips/UroNav, Eigen/Artemis, Koelis/Urostatin, Hitachi/HI-RVS, and GeoScan/BioJet systems have been developed and put into use. These devices were developed due to the difficulty of performing biopsy under direct MRI (Figure 3).

CONCLUSION Radiology is developing rapidly. In the near future technological advances in diagnostic radiology, minimal invasive radiology and artificial intelligence will benefit the radiologists and patients alike. Peer-review: Externally peer-reviewed.

Figure 3. Mp-MRI for prostate cancer localization in the apex and in the right zone in a 60-year-old man. After these lesions were marked in fusion images, targeted biopsy was performed with exact accuracy

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Author Contributions: Concept - S.A., H.Ö.; Design - H.Ö., R.Y.B.; Supervision - H.Ö., S.A.; Data Collection and/or Processing - S.A., H.Ö.; Analysis and/or Interpretation - H.Ö., S.A., R.Y.B.; Literature Search S.A., R.Y.B.; Writing Manuscript - H.Ö., R.Y.B.; Critical Review - H.Ö., S.A.

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Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Compared to previous generations of Magnetom 7T; data on file. 2. Research mode is still under development and not commercially available in the U.S. and other countries. Its future availability cannot be ensured. 3. Paiva OA, Prevedello LM. The potential impact of artificial intelligence in radiology. Radiol Bras 2017; 50: 5-6. 4. Serhatlıoğlu S, Hardalaç F. Yapay zeka teknikleri ve radyolojiye uygulanması. Fırat Tıp Derg 2009; 14: 1-6. 5. Leung SC, Fulcher J. Classification of user expertise level by neural networks. Int J Neural Syst 1997; 8: 155-71. 6. Atacak Đ. Genel Amaçlı Bir Bulanık Mantık Denetleyicinin Tasarımı. Gazi Üniversitesi Fen Bilimleri Enstitüsü Yüksek Lisans Tezi 1998; 71. 7. Ergezer H, Dikmen M, Özdemir E. Yapay sinir ağları ve tanıma sistemleri. PiVOLKA 2003; 2: 14-7.

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9. 10.

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Rafiee A, Moradi MH, Farzaneh MR. Novel genetic-neurofuzzy filter for speckle reduction from sonography images. J Digit Imaging 2004; 17: 292-300. Kohli M, Prevedello LM, Filice RW, Geis JR. Implementing Machine Learning in Radiology Practice and Research. AJR 2017; 208: 754-60. Bonekamp D, Jacobs MA, El-Khouli R, Stoianovici D, Macura KJ. Advancements in MR Imaging of the Prostate: From Diagnosis to Interventions. RadioGraphics 2011; 31: 677-703. Hakan Gençhellaç, Erdem Yılmaz. Prostat görüntüleme. Trd Sem 2015; 3; 138-45. Vural M, Onay A, Acar Ö, Erol M, Çolakoğlu B, Avcı A. Prostat kanserinde multiparametrik MRG yönteminin kullanılması. Siemens e-dergi, Radyoloji Özel Sayısı 2013: 46-8. Barentsz JO, Richenberg J, Clements R, Choyke P, Verma S, Villeirs G, et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746-57. Röthke M, Blondin D, Schlemmer HP, Franiel T. PI-RADS classification: structured reporting for MRI of the prostate. Rofo 2013; 185: 253-61. Turkbey B, Pinto PA, Choyke PL. Imaging techniques for prostate cancer: implications for focal therapy. Nat Rev Urol 2009; 6: 191203.

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Fluorescence in Situ Hybridization in Pathology Özben Yalçın

, Gamze Kulduk

Department of Pathology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Fluorescence in Situ Hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes which bind to specific chromosomal locations within the nucleus to search and detect chromosomal abnormality. In the last decade, tumor-specific chromosomal translocations, deletions, gains, amplifications, and novel oncogenes have become increasingly important in the field of diagnostic, therapeutic, and prognostic concepts in medicine. FISH technique provides a quick analysis of formalin-fixed paraffin-embedded cells which can be used in daily practice of pathology for several tumor types. Fluorescence in Situ Hybridization (FISH) technique is based on hybridization of tagged DNA probes which are fluorescent reporter molecules that affirm the presence or absence of particular genetic anomaly under fluorescence microscopy. This technique has been recently developed to screen the whole genome coexistently through multicolor whole chromosome probe techniques that multiplex-FISH or spectral-karyotyping or through an array-based method using comparative genomic hybridization. The aim of this article was to provide a theoretical survey of FISH for clinical function in surgical pathology habit. Keywords: FISH, molecular genetics, pathology

INTRODUCTION

ORCID IDs of the authors: Ö.Y. 0000-0002-0019-1922; G.K. 0000-0001-9071-651X Cite this article as: Yalçın Ö, Kulduk G. Fluorescence in Situ Hybridization in Pathology. Eur Arch Med Res 2018; 34 (Suppl. 1): S46-S47. Corresponding Author: Özben Yalçın E-mail: ozbena@yahoo.com Received: 26.08.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.81300 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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Fluorescence in situ hybridization technique is based on fluorescence-labeled fragments of DNA binding to interphase chromosomes of cytology materials or paraffin-embedded tissue segments. Chromosome deletions, gains, translocations, amplifications, and polisomy of certain types of tumors can be detected by FISH, which are useful in diagnostic and therapeutic purposes (1, 2). Recently it has been found that more than 30% of soft tissue sarcomas have specific translocations and more than 30 subtypes of mesenchymal tumor can be affirmed via FISH analysis on the basis of tumor specific chimeric fusion cycles (3). These include Ewing sarcoma, myxoid liposarcomas, synovial sarcomas, solitary fibrous tumors, inflammatory myofibroblastic tumors, and alveolar rhabdomyosarcomas (4-8). Chromosomal translocations that are associated with ordinary adult epithelial tumors are as follows: adenocarcinomas of the lung, prostate, colon, kidney, breast, colorectal, thyroid, and salivary gland. EML4-ALK Translocation The ALK fusion oncogenes were first named in an anaplastic large-cell lymphoma, wherein a T(2;5) chromosome rearrangement activates the ALK kinase by fusion with the NPM1 on chromosome 5 ALK fusions have been announced in non-small cell lung carcinoma, breast cancers, colorectal cancers, renal cancers, and other tumor types (9). FISH test for ALK rearrangement uses dual color labeled probes of the ALK gene and 3’ region of ALK. When FDA approved a new anticancer drug and its FISH detection kit (ALK FISH PROBE KIT) in 2013, EML4-ALK translocation-targeted therapy became crucial for patients with lung cancer and in surgical pathology practice (10). ROS1 Translocation ROS1 is a receptor tyrosine kinase of the insulin receptor group like ALK which is detected in 1.2%-1.7% of lung adenocarcinoma cases (11). ROS1 translocations have been found in young,

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nonsmoker patients with high-grade lung adenocarcinoma. A dual-probe break-apart method is used to detect ROS1 translocations similar to ALK. TFE-3 Translocation Renal cell carcinomas associated with Xp11.2 translocation are newly described renal tumors in the new who book (12). TFE3 break-apart FISH probe is reportedly more useful compared with immunohistochemistry for detecting TFE3 gene fusions in Xp11.2 translocation renal cell carcinoma. Rao et al. (12) proved the diagnostic value of TFE-3 in renal cell cancers by showing 17 of 24 unclassified renal cell cancers had TFE-3 rearrangement associated with Xp11.2 translocation by FISH. TMPRSS2-ERG Gene Fusion These fusions have been identified in approximately 50% of prostate tumors (ranging from 27% to 79%) and are also found in high-grade prostatic intraepithelial neoplasia, which may play a role in early development in prostatic carcinogenesis. The TMPRSS2-ERG gene fusion can be identified by both dual and tricolor probes (13). HER-2/Neu Amplification HER-2 also called c-erbB-2 is a tyrosine kinase which plays part in normal cell growth. Amplification and over-expression of the HER-2/neu gene occurs in 25%-30% of human breast cancers with a poor clinical prognosis and short survival time. Presently, HER-2 overexpression can be shown by immunohistochemistry and FISH technique. Because immunohistochemistry is a cheap and easier way than FISH, it is used when IHC results are borderline (14). 1p19q Co-Deletion In the new who book of central nervous system 2016, it is recommended that a pathology report should contain molecular diagnosis. 1p19q co-deletion is characteristic for oligodendrogliomas that can be shown by FISH (15). Fluorescence in Situ Hybridization (FISH) identification of chromosomal translocations has diagnostic, therapeutic, and prognostic use in lymphoma, colorectal carcinoma, thyroid carcinoma, Spitz nevi, melanoma, and salivary gland tumors (16). The most commonly used FISH methods in differential diagnosis of small B cell lyphoma are the translocation of IgH-Cyclin D1 t(11; ,14) (q13;q32) for mantle cell lymphoma; translocation of t(14;18) (q32;q21) for follicular lymphoma; translocation t(8;14) (q24;q32) for burkitt lymphoma; and translocation of BCR-ABL for chronic myeloid leukemia.

CONCLUSION Fluorescence in Situ Hybridization (FISH) analysis of neoplasms has become one of the most interesting and improving areas in surgical pathology in the last decade. Nowadays, diagnostic and treatment choices are designated by FISH for many tumor types. The technology of FISH analyses of chromosomal alterations is rapidly evolving in the 21th century. The role of FISH in cancer diagnosis and treatment will become more significant in surgical pathology practice.

Peer-review: Externally peer-reviewed.

Yalçın and Kulduk. Fluorescence in Situ Hybridization

Author Contributions: Concept - Ö.Y., G.K.; Design - Ö.Y., G.K.; Supervision - Ö.Y., G.K.; Data Collection and/or Processing - Ö.Y., G.K.; Analysis and/or Interpretation - Ö.Y., G.K.; Literature Search - Ö.Y., G.K.; Writing Manuscript - Ö.Y., G.K.; Critical Review - Ö.Y., G.K. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Cheng L, Zhang DY, Eble JN. Molecular Genetic Pathology (2nd edn). Springer: New York, NY, 2013. 2. Cheng L, Eble JN. Molecular Surgical Pathology (1st edn). Springer: New York, NY, 2013. 3. Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F (Eds). WHO/IARC Classification of Tumours, 4th Edition, Volume 5. IARC Press, Lyon, 2015. 4. Thway K, Fisher C. Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions. The current status. Am J Surg Pathol 2012; 36: 1-11. 5. Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov 2015; 5: 124-34. 6. Mohajeri A, Tayebwa J, Collin A, Nilsson J, Magnusson L, von Steyern FV, et al. Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene,nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes Chromosomes Cancer 2013; 52: 873-86. 7. Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 2013; 13: 685700. 8. Thway K, Rockcliffe S, Gonzalez D, Swansbury J, Min T, Thompson L, et al. Utility of sarcoma-specific fusion gene analysis in paraffin-embedded material for routine diagnosis at a specialist centre. J Clin Pathol 2010; 63: 508-12. 9. Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr, Wu YL, et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017; 389: 299-311. 10. Alkan A, Koksoy EB, Utkan G. First-line crizotinib in ALK-positive lung cancer. N Engl J Med 2015; 372: 781-2. 11. Uguen A, De Braekeleer M. ROS1 fusions in cancer: a review. Future Oncol 2016; 12: 1911-28. 12. Rao Q, Williamson SR, Zhang S, Eble JN, Grignon DJ, Wang M, et al. TFE3 greak-apart FISH has a higher sensitivity for Xp11.2 translocation-associated renal cell carcinoma compared with TFE3 or cathepsin K immunohistochemical staining alone: expanding the morphologic spectrum. Am J Surg Pathol 2013; 37: 804-15. 13. Williamson SR, Zhang S, Yao JL, Huang J, Lopez-Beltran A, Shen S, et al. ERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin. Mod Pathol 2011; 24: 1120-7. 14. Pauletti G. William Godolphin More Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. 15. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK: WHO classification of tumours of the central nervous system, ed 4 Lyon, IARC Press, 2016. 16. Amelio AL, Fallahi M, Schaub FX, Zhang M, Lawani MB, Alperstein AS, et al. CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 2014; 111: 3260-8.

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Wearable Kidney; Away from Tomorrow but More Real than Dream Mehmet Küçük Department of Internal Medicine, University of Health Sciences, Okmeydanı Health Application and Research Center, İstanbul, Turkey

Abstract A wearable kidney is a device that can relieve patients with renal failure of dialysis. This wearable kidney can be worn on the waist like a belt. It removes the harmful substances from the blood and removes excess water and salt from the body. Keywords: Wearable kidney, patient, tecnology

INTRODUCTION Over the past two decades, the number of dialysis patients in the world has doubled. Among them, 80% are treated with hemodialysis (1, 2). In our country, the spot prevalence of end-stage renal disease that requires renal replacement therapy is 933 per million population, with an incidence of 140. However, in recent years, these figures have reached a plateau (3). In Turkey in 2016, there were 56,687 (70.12%) hemodialysis patients, 3508 (19.17%) renal transplantation patients, and 368 (0.64%) patients receiving hemodialysis treatment at home (3). Despite technological advances in renal replacement therapies, unacceptable high mortality and poor quality of life persist (4). Although home hemodialysis positively contributes to patient survival, it has its disadvantages such as wide area occupation of dialysis equipment, high-energy costs, and substantial water use (5). ORCID ID of the author: M.K. 0000-0003-1720-3819 Cite this article as: Küçük M. Wearable Kidney; Away from Tomorrow but More Real than Dream. Eur Arch Med Res 2018; 34 (Suppl. 1): S48-S50. Corresponding Author: Mehmet Küçük E-mail: mdmkucuk@gmail.com Received: 14.10.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.83803 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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Although kidney transplantation is the best choice in the treatment of end-stage renal disease, it is not possible to respond to all patients due to organ limitation and naturally extending waiting list (2). Therefore, for the treatment of patients with CKD5d, efforts are being made to develop wearable and implantable devices that can increase not only patient survival but also quality of life in the near and distant future (4). While the dream of a wearable kidney was first mentioned in the 1970s, the first animal experiments were carried out in 2005 and human studies in 2007 (6, 7). The wearable kidney should be able to regulate the blood pressure by providing the patient’s volume control, and it should be able to provide toxic metabolites of the patient without applying challenging diet programs and reduce the need for medication (8, 9). At the same time, there should be time and cost advantages according to hemodialysis performed at the center (10). For wearable kidneys, three difficult challenges to be overcome are the life of the device, power supply, and the removal of waste materials (4). For a successful wearable kidney, the glomerular membrane should be attached to a tubule membrane designed to re-absorb the ultrafiltrate. Thus, they can provide sufficient nitrogen excretion with only 2 L of filtrate per day. A method similar to that in the reverse osmosis water system can be developed for a tubule membrane that is capable of re-absorbing water and solutes. It can be designed in a way to distinguish which solutes will be reabsorbed and separated, and whether separation has occurred or not (4). In a standard dialysis session, 240 L of ultrapure fluid should be produced and removed again. It is impossible to process all these high amounts by means of a device carried on human. Therefore, newer technology is needed (4). Dialysate regeneration with absorbent substances has long been used to minimize water requirements, but when they are saturated for each process, they require fresh

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reagents. This limits the applicability of sorbent technology to implantation devices (4). Because wearable kidney will control the complications arising from extracorporeal blood circulation, which should often be opened and closed and will reduce the risk of infection, it can provide more applicability (4). Two pilot studies have been presented so far (7, 8). The first one was published in Italy in 2008, and ultrafiltering efficiency was proven in congestive heart failure (11). In six hemodialysis patients, ultrafiltration was achieved at a rate of 120-288 mL/h for 4-6h, and the respiratory and circulatory systems of these patients remained stable in these sessions (11). The second study was performed in eight patients in the UK. The prototype instrument was tried for 4-8h, and the arteriovenous (AV) fistulas that were always used as the vascular access were used in patients (12). Gura and his team, who were the most experienced in the development of wearable kidneys, developed the first ultrafiltration instrument, and they were able to apply first wearable hemodialysis that could be used for 24h in 2016 (4, 7). Vascular access is the most critical problem for wearable kidneys because coagulation problems are often encountered in classical AV fistulas. Synthetic grafts seem to be more successful in this regard (4). Hemaport (Hemapure, Uppsala, Sweden) has developed a needle that includes a titanium connector connected to the polytetrafluoroethylene graft, and does not require an AV fistula (13). Life-Site valve, another alternative that includes titanium, stainless steel, and silicon elements attached to the 12-Fr silicone cannula has been developed. It is placed in the central venous system (14). Other important problems to be overcome are dialysis membranes, dialysate regeneration, power supply, and pump systems. A certain progression has been achieved on this issue (15). In an article published in 2011 (16), three leading researchers in the field predicted that the following conditions should be met in order to have an ideal wearable artificial kidney. • The vascular bed should be able to provide a continuous flow of 100 mL per minute. • The risk of infection should be low. The patient should not have any problem while it is connected or disconnected. A small amount of dialysate solution should be sufficient and reusable. There should be no clotting during the procedures of dialysis. Solute clearance should be 20 mL per second, and ultrafiltration should not be more than 5 mL per minute. • There should also be fast and safe warning systems for air embolism, and these systems should be able to be applied quickly by the patient when necessary. Urea clearance is another challenge in the design of wearable artificial kidneys. For this, it seems to be inevitable to develop a system that allows the dialysate to be used repeatedly (16). Developments in material technology enable transition from silicon-based catheters to polyurethane-based catheters. In fact,

Küçük M. Wearable Kidney

both silicon and polyurethane catheters have similar life span and functionality, but polyurethanes are more resistant to pressure and allow more blood to be transported by decreasing material thickness (17). Parallel to the development of nanotechnology, understanding of the key role of the fibrin sheath in the development of CVCassociated thrombosis and bacteremia has led to the emergence of highly promising CVC coatings. In a recently published in-vitro study, Hugoni et al. evaluated fibronectin, monocyte response, and thrombus formation on two-surface modified polyurethane (18). Advances in nanotechnology will allow the addition of macromolecules inside and outside of the catheter, and the coagulation problem can be reduced (4). ESSENCE The ideal wearable kidney should be comfortable, and it should not interfere with everyday life (10, 12, 19). Many technical problems to be overcome continue to exist for wearable kidneys. The development of an economically accessible wearable kidney seems to be far away yet (16). Although it took more than 50 years to develop the prototype of a wearable artificial kidney for the treatment of patients with CKD5d, the clinical studies of two devices that function as hemodialysis and PD have already begun. The success of these devices will depend not only on the removal of solutes but also on the ability to protect electrolyte, acid-base, and volume homeostasis, and on the tolerance of patient (5). As a result, wearable kidney seems to be away from tomorrow, but more real than dream. Peer-review: Externally peer-reviewed. Conflict of Interest: The author has no conflicts of interest to declare. Financial Disclosure: The author declared that this study has received no financial support.

REFERENCES 1. Thomas B, Wulf S, Bikbov B, Perico N, Cortinovis M, Courville de Vaccaro K, et al. Maintenance dialysis throughout the world in years 1990 and 2010. J Am Soc Nephrol 2015; 26: 2621-33. 2. Liyanage T, Ninomiya T, Jha V, Neal B, Patrice HM, Okpechi I, et al. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet 2015; 385: 1975-82. 3. Türkiye Ulusal Nefroloji, Diyaliz ve Transplantasyon (TND) Kayıt Sistemi Raporu (2016). Availablef from: http://www.tsn.org.tr/folders/file/registry_kitabi_2016.pdf 4. Gura V, Rivara MB, Bieber S, Munshi R, Smith NC, Linke L, et al. A wearable artificial kidney for patients with end-stage renal disease. JCI insight 2016; 1. 5. Fissell WH, Roy S, Davenport A. Achieving more frequent and longer dialysis for the majority: wearable dialysis and implantable artificial kidney devices. Kidney Int 2013; 84: 256-64. 6. Gura V, Beizai M, Ezon C, Polaschegg HD. Continuous renal replacement therapy for end-stage renal disease. The wearable artificial kidney (WAK). Contrib Nephrol 2005; 49: 325-33. 7. Davenport A, Gura V, Ronco C, Beizai M, Ezon C, Rambod E. A wearable haemodialysis device for patients with end-stage renal failure: a pilot study. Lancet 2007; 370: 2005-10.

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8. Gura V, Davenport A, Beizai M, Ezon C, Ronco C. Beta2microglobulin and phosphate clearances using a wearable artificial kidney: a pilot study. Am J Kidney Dis 2009; 54: 104-11. 9. Ronco C, Davenport A, Gura V. The future of the artificial kidney: moving towards wearable and miniaturized devices. Nefrologia 2011; 31: 9-16. 10. Davenport A. Portable and wearable dialysis devices for the treatment of patients with end-stage kidney failure: Wishful thinking or just over the horizon? Pediatr Nephrol 2015; 30: 2053-60. 11. Gura V, Ronco C, Nalesso F, Brendolan A, Beizai M, Ezon C, et al. A wearable hemofilter for continuous ambulatory ultrafiltration. Kidney Int 2008; 73: 497-502. 12. Davenport A, Ronco C, Gura V. From wearable ultrafiltration device to wearable artificial kidney. Contrib Nephrol 2011; 171: 237-42. 13. Ahlmen J, Goch J, Wrege U, Larsson R, Honkanen E, Althoff P, Danielson BG. Preliminary results from the use of new vascular access (Hemaport) for hemodialysis. Hemodialysis Int 2003; 7: 73-104.

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14. Levin NW, Ronco C. Hemodialysis Vascular Access and Peritoneal Dialysis Access. Vicenza: Karger; 2004. 15. Armignacco P, Lorenzin A, Neri M, Nalesso F, Garzotto F, Ronco C. Wearable devices for blood purification: principles, miniaturization, and technical challenges. Semin Dial 2015; 28: 125-30. 16. Topfer LA. (2017). Wearable Artificial Kidneys For End-Stage Kidney Disease. Cadth Issues In Emergıng Health Technologıes ISSN: 1488-6324 (Online) 17. Tal MG, Ni N. Selecting optimal hemodialysis catheters: material, design, advanced features, and preferences. Tech Vasc Interv Radiol 2008; 11: 186-91. 18. Hugoni L, Montano-Machado V, Yang M, Pauthe E, Mantovani D, Santerre JP. Fibronectin adsorption on surface-modified polyetherurethanes and their differentiated effect on specific blood elements related to inflammatory and clotting processes. Biointerphases 2016; 11: 029809. 19. Armignacco P, Garzotto F, Neri M, Lorenzin A, Ronco C. Wak engineering evolution. Blood Purif 2015; 39: 110-4.

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Use of the Robots, Virtual Reality and Other Technological Devices in Rehabilitation Sevgi Atar

, Berrin Hüner

, Ömer Kuru

Clinic of Physical Medicine and Rehabilitation, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Robotic systems, virtual reality, transcranial magnetic stimulation and telecommunication technologies have been safely used in rehabilitation of traumatic brain-spinal injuries, stroke, motor neuron diseases, fibromyalgia, Parkinson’s disease, and balance disorders. Their benefits from the point of view of scientific studies include the properties of a reliable test environment, gradual exposure to stimuli, simultaneous performance reporting, stimulus and response modifications, independent application chance, stimulus control and consistency, distraction or enhancement of the patient’s attention, and patient motivation. It would be inevitable to benefit from these technologies, which are economical, and for which access to rehabilitation is facilitated as a result of further worldwide increase in the elderly population and it would be useful technologies such as include robotics, virtual reality and magnetic stimulation used in rehabilitation of health professionals in their education programs. Keywords: Robotic, rehabilitation, virtual reality, magnetic stimulation

INTRODUCTION ORCID IDs of the authors: S.A. 0000-0003-3767-7448; B.H. 0000-0003-3584-8880; Ö.K. 0000-0001-5677-3924 Cite this article as: Atar S, Hüner B, Kuru Ö. Use of the Robots, Virtual Reality and Other Technological Devices in Rehabilitation. Eur Arch Med Res 2018; 34 (Suppl. 1): S51-S54. Corresponding Author: Sevgi Atar E-mail: sevgiatar@gmail.com Received: 30.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.64936 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Technological innovations used in the field of rehabilitation have increasingly taken place in the last few decades. Transcranial magnetic stimulation (TMS), robotic systems, virtual reality (VR), and telecommunication technologies, which have spread and developed in this electronic and information age in association with scientific developments, are also used in the field of rehabilitation in the developed and developing countries (1-4). Robotic rehabilitation (RR) systems, including computer-based electromechanical devices are used in rehabilitation, particularly in neuro-rehabilitation because they are intensive, repetitive, interactive, and sustainable which is therapist-independent. Hemiplegia, stroke, and upper extremity motor diseases are the main disease groups with the possibility of rehabilitation (1, 3, 4). Although this rehabilitation programs are increasingly used in developed countries having appropriate infrastructure, difficulties in accessing these systems by developing countries and the lack of more scientific studies on this rehabilitation programs became obstacle for wide spreade of this rehabilitation programs (4, 5). Today, three-dimensional systems have been developed so that we can perceive the real-world sections through visual, auditory, and tactile by means of glasses or closed platforms. They are used in healthcare as well as in civil and military education and for recreational purposes. They have a key importance in rehabilitation by providing patient adaptation to exercises, repeatability, and objective measurement of the effort by creating alternative visual environments that can be reached in a more economical manner (6, 7). Transcranial magnetic stimulation was first used for major depression treatment subsequently it found a place in the field of rehabilitation. TMS acts by creating depolarization, neural plasticity, and evokes responses on the brain parenchymal neurons with electrical stimulation created by

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electromagnetic field. TMS therapy is used in cases, such as fibromyalgia syndrome, neuropathic pain, and Parkinsonâ&#x20AC;&#x2122;s disease, in which a response cannot be achieved with classical therapies (8-10). Increased telecommunication technologies are beneficial for patients with transportation problems or with fewer mobilization opportunities, and for the sustainability of treatment after discharge. Thus, the patient can be followed without the physicianâ&#x20AC;&#x2122;s presence, and treatment options can be provided (2, 4, 5). Many inventions, such as wireless brain and extremity implants with artificial intelligence, smart watches, smart wearable items, musculoskeletal tracking devices, smart prostheses, stem-cell implants, and package cardiac rehabilitation systems have been developed to enhance rehabilitation practices (4, 5, 10). With the increasing elderly population worldwide, it would be inevitable to use economical technologies, for which access to rehabilitation is facilitated (5, 10, 11). Robotic Rehabilitation Since the last quarter of the twentieth century, robotic technologies have increasingly started to take place in the sectoral basis. They are also used as an auxiliary method in the field of rehabilitation. RR is especially utilized in patients who need intensive support in neurorehabilitation. Because the force and resistance parameters can be programmed in RR, it supports the rehabilitation techniques applied to the patient, decreases the physical efforts of the therapist, and provides accurate feedback. It facilitates patient compliance with the therapist to increase the number of movements. It allows patients to perform their movements with gradual autonomy (1, 3, 4). Although it reduces the number of therapists needed, it helps in increasing the number of patients that are given therapy and the duration of therapy. It provides active participation in treatment by increasing the motivation of patients under objective feedback data. In the computer-assisted RR, the treatment protocol stored in the memory can be applied to the patient by the robotic mechanism, after the first movement of the therapist. Duration, the number of repetitions, and speed can be altered by the therapist from outside. It is also possible to motivate the patient to perform movements by showing a target with visual objects (1-4, 10, 11). Besides regulating the rehabilitation process and improving therapeutic outcomes, robotic technologies have the potential to support clinical evaluation, to completely control therapy, to measure, and to apply new forms of mechanical manipulation by therapists. The wellknown robotic platforms are hand-arm-shoulder, robotic bed-wheelchair, walking, and isokinetic exercise systems (Cybex II). All these systems can be programmed and adjusted according to the pathology of the muscle and joint movements of the patient (4, 5, 10). According to their usage areas, they are classically handled as lower and upper extremity robots. RR was first used on the lower extremities. However, the success rates of upper extremity applications are higher. In upper extremity applications, the

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success rates for hand, wrist, and finger movements are lower than those for the other components of upper extremity. For example, the wrist pronation and supination, and elbow flexion and extension in the upper extremity provide a new approach for strength and movement improvement in assisted physiotherapy. Passive, active, and assisted exercise programs can be applied. Moreover, feedback on proprioceptive state and force information is obtained. In patients with hemiplegia and cerebral palsy, it recreates a situation that is as similar as possible to a real walking pattern for the lower extremity, and encourages patients to control different movements related to walking. It can create synergy not only in the individual movements of the lower extremity joints but also in the upper body, and it provides an appropriate posture. Studies have reported that passive and active movements that can be programmed in robotic systems are beneficial in the treatment of hemiplegia or motor diseases by regulating resistance to movements (1, 3, 11). Besides that, these systems can be applied together with conventional methods right from the beginning of treatment (2, 4, 10). Virtual Reality Since their introduction by J. Lanier in the late 1980s, computers have begun to produce realistic, more detailed, and fast three-dimensional images. The VR technology gives us the opportunity to revive the complex physical state of the real world in a controlled environment of the laboratory. It has the potential to measure and adjust complex movements on request in natural environments. The VR products are available in different designs from head-mounted visual data devices to cabinet designs. Basically, they work with the same logic, but in practice they are different. In some of the glass-type VR devices, communication with the outside world is interrupted, and the visuals produced by the computers are seen. In some of them, the modellings produced by the computers are created as projections on real environments. In the cabinet designs, the image generated by the computers is reflected on a surface in front of the cabinet and the simulation is performed. In this application, the field of view is limited according to the glasses-type systems. Another platform is projection-based systems. They create a three-dimensional image by projecting the produced image onto a surface or screen in cinema-like environments. These systems generally have a wide field of view and can be used by reflecting on multiple surfaces (2, 4, 11). The introduction of all these technologies in rehabilitation dates back to the early 1990s. Scientific studies are being published with increasing momentum. Accessing the environments, which have high economic cost and which we cannot easily reach in real life, by the help of computers and low cost has paved a way for VR applications in rehabilitation (2, 4, 11, 12). What are the advantages of VR applications for health practitioners? VR applications have many advantages for health practitioners such as being independently applicable, reliable test environment, graded and controled exposure to stimuli, concurrent performance reporting, ability to do modifications on stimulus and

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response also it provides advantages that are reported in the literature, such as distracting or enhancing patient motivation. (11-13). Using virtual environments and reality, it offers the opportunity to work on motor rehabilitation and, wherever possible, compare them to the results obtained in controlled realworld applications (13, 14). Particularly traumatic cerebrospinal injuries and stroke rehabilitation are used in orthopedic rehabilitation of patients with Parkinson’s disease and rehabilitation of balance disorders. Studies suggest that it facilitates rehabilitation adjustment problems in pediatrics (2, 4, 5, 11-13). Transcranial Magnetic Stimulation Transcranial magnetic stimulation is a non-invasive neurophysiological application. It is based on the principles of electromagnetic stimulation defined in the last quarter of the twentieth century and developed over time. Earlier, repetitive TMS (rTMS) application was used for treating patients with resistant major depression, and it later became widespread after Food and Drug Administration approval. In the later years, it has also been used in chronic pain, tinnitus, movement disorders, and obsessive compulsive disorders. This technique is performed by stimulating the cortical areas of the brain by electrical stimuli placed on the scalp. With the help of electrical coil, electromagnetic field is created with fast and variable frequencies. With the help of electrodes from a short distance, this area is expected to act on the brain parenchyma by converting to electrical stimulation. The magnetic field itself does not directly stimulate the tissue, but the amplitude of the induced current generates action potential leading to depolarization in the nerve membrane if the spatial characteristics and duration are sufficient. TMS acts by depolarizing neurons, providing neural plasticity, or generating stimulated responses. It can be used for diagnostic, prognostic, and therapeutic purposes. In diagnostic use, the findings determined by TMS are not disease specific and should be evaluated with other clinical information. In therapeutic applications, the cortical excitability reduces in low-frequency and increases in high-frequency applications of repetitive rTMS (8, 9, 15). Transcranial magnetic stimulation is used in fibromyalgia syndrome, stroke, neuropathic pain, multiple sclerosis, and Parkinson’s disease. It also activates the motor units of the related muscle groups by acting on the affected area of the brain parenchyma after stroke. It has an impact on motor cortex by displaying functional increase in Parkinson’s disease. In neuropathic pain, TMS is suggested to provide a regulatory effect on the central and peripheral neural pathways. In addition to the potential beneficial effects, TMS has been reported to affect the intact parenchyma of the brain and have temporary central side effects, such as epilepsy, headache, and hearing loss (8, 9, 15). Telecommunications Technologies They are technologies facilitating the follow-up of discharged patients, who underwent rehabilitation at home. They facilitate the access of the patient groups who have difficulty in reaching rehabilitation centers and the patients in elderly care centers to have access to rehabilitation (2, 4, 5, 10).

Atar et al. Use of Technological Devices in Rehabilitation

CONCLUSION The introduction of robotic-device-based techniques in physical rehabilitation and TMS and VR applications has been shown to contribute to treatment and increase in patient compliance. Since it is envisaged that these approaches will be more widespread in parallel with technological developments, especially in the areas of neurorehabilitation and stroke rehabilitation, it would be useful if the trainings of health professionals are accordingly planned. Peer-review: Externally peer-reviewed. Author Contributions: Concept - S.A.; Design - S.A.; Supervision - S.A.; Data Collection and/or Processing - S.A.; Analysis and/or Interpretation - S.A.; Literature Search - B.H.; Writing Manuscript - S.A.; Critical Review - Ö.K. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

REFERENCES 1. Ferreira FMRM, Chaves MEA, Oliveira VC, Van Petten AMVN, Vimieiro CBS. Effectiveness of robot therapy on body function and structure in people with limited upper limb function: A systematic review and meta-analysis. Martinuzzi A, ed. PLoS ONE. 2018; 13: e0200330. 2. Sivakumar S, Taccone FS, Desai KA. ESICM LIVES 2016: part two: Milan, Italy. 1-5 October 2016. Intensive Care Medicine Experimental 2016; 4(Suppl 1): 30. 3. MJ Lee, JH Lee, Lee SM. Effects of robot-assisted therapy on upper extremity function and activities of daily living in hemiplegic patients: A single-blinded, randomized, controlled trial. Technol Health Care 2018 A. doi: 10.3233/THC-181336. 4. Siekierka EM, Eng K, Bassetti C, Blickenstorfer A, Cameirao MS, Dietz V, et al. New technologies and concepts for rehabilitation in the acute phase of stroke: a collaborative matrix. Neurodegener Dis 2007; 4: 57-69. 5. Hassett L, van der Berg M, Lindley RI, Crotty M, McCluskey A, van der Ploeg HP, et al. Effect of affordable technology on physical activity levels and mobility outcomes in rehabilitation: a protocol for the Activity and MObility UsiNg Technology (AMOUNT) rehabilitation trial. BMJ Open 2016; 6: e012074. 6. Keshner EA. Virtual reality and physical rehabilitation: a new toy or a new research and rehabilitation tool? J Neuroeng Rehabil 2004; 1:8. doi:10.1186/1743-0003-1-8. 7. Laver KE, George S, Thomas S, Deutsch JE, Crotty M. Virtual reality for stroke rehabilitation. Cochrane Database Syst Rev 2011; DOI: 10.1002/14651858. 8. Çakar E. Neuromodulation in Fibromyalgia Syndrome: Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation. Turkiye Klinikleri J PM&R-Special Topics 2014; 7: 72-4. 9. Schuber M, Dengler R, Wohfarth K, Elek J, Stallkamp A. Activation of high-threshold motor units in man by transcranial magnetic stimulation. Neurosci Lett 1993; 150: 21-4. 10. Schenk P., Colombo G., Maier I. (2013) New Technology in Rehabilitation: Possibilities and Limitations. In: Pons J., Torricelli D., Pajaro M. (eds) Converging Clinical and Engineering Research on Neurorehabilitation. Biosystems & Biorobotics, vol 1. Springer, Berlin, Heidelberg.

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11. Van den Berg M, Sherrington C, Killington M, Smith S, Bongers B, Hassett L, et al. Video and computer-based interactive exercises are safe and improve task-specific balance in geriatric and neurological rehabilitation: a randomised trial. J Physiother 2016; 62: 20-8. 12. Yavuzer G, Senel A, Atay MBG, Stam HJ. â&#x20AC;&#x153;Playstation eyetoy gamesâ&#x20AC;? improve upper extremity-related motor functioning in subacute stroke: A randomized controlled clinical trial. Eur J Phys Rehabil Med 2008; 44: 237-44. 13. Kang SH, Kim DK, Seo KM, Choi KN, Yoo JY, Sung SY, et al. A computerized visual perception rehabilitation programme with interac-

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tive computer interface using motion tracking technology - a randomized controlled, single-blinded, pilot clinical trial study. Clin Rehabil 2009; 23: 434-44. 14. Rizzo AA, Kim G. A SWOT analysis of the field of virtual rehabilitation and therapy. Presence: Teleoperators and Virtual Environments 2005; 14: 119-46. 15. Galhardoni R, Correia GS, Araujo H, Yeng LT, Fernandes DT, Kaziyama HH. Repetitive transcranial magnetic stimulation in chronic pain: a review of the literature. Arch Phys Med Rehabil 2015; 96: 156-72.

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Recent Technological Advances in Radiotherapy Özge Kandemir Gürsel Department of Radiation Oncology, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey

Abstract Intense and rapid technological advances in computer software, imaging and engineering projected to radiotherapy over the past decades. As the main objective of radiotherapy is sterilization of tumor cells at a defined target with adequate safety margins, treatment planning and dose delivery systems allowed the precise radiation dose to the target volume, sparing the adjacent structures. The breakthrough development of computer-controlled multileaf collimators and adaptation of computer tomography-based planning enabled three-dimensional conformal therapy. Intensity-modulated radiotherapy, volumetric modulated arc therapy, image-guided radiotherapy, adaptive radiotherapy, stereotactic radiotherapy, intraoperative radiotherapy, brachytherapy, charged particle radiotherapy, and hyperthermia are the technological reflection of these improvements. As radiotherapy is one of the most technology-driven treatment modalities in the management of cancer, future innovations and knowledge gained from clinical trials will help to improve new treatment strategies. Keywords: 3D conformal radiotherapy, intensity-modulated radiotherapy, image guided radiotherapy, stereotactic radiotherapy, intraoperative radiotherapy, proton beam radiotherapy

INTRODUCTION

ORCID ID of the author: Ö.K.G. 0000-0002-6960-4115 Cite this article as: Kandemir Gürsel Ö. Recent Technological Advances in Radiotherapy. Eur Arch Med Res 2018; 34 (Suppl. 1): S55-S60. Corresponding Author: Özge Kandemir Gürsel E-mail: drozgekandemir@gmail.com Received: 29.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.69775 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Radiotherapy is an important component of cancer treatment that remains as an integral part for local control. Delivering high dose to the tumor region is important for treatment achievement while the complications also increase with the dose given to the region of the organ irradiated. Over the past decade, advances in technology leading significant developments at computer software and imaging algorithms, sophisticated dose calculation methods in radiotherapy planning, and delivery techniques have allowed adaptation to tumor volume with better tumor delineation, decreasing nearby normal tissue irradiation while increasing targeted tumor dose accurately with the opportunity of improved survival. Conformal Radiotherapy In the early 1970s, the introduction of computer tomography (CT) was a key to the development of the modern three-dimensional (3D) planning that is crucial to conformal therapy because it made available a complete 3D description of the anatomy of each patient that could be the basis for planning (1). Similar to CT, magnetic resonance imaging (MRI) and positron emission tomography (PET) have also replaced plain radiography in radiation treatment planning for their direct visualization of soft tissue structure and tumors with precise location in defining the target volume. Conformal therapy describes radiotherapy treatment that aims high-dose volume shaped to closely “conform” to target volumes while minimizing the dose to critical normal tissues. Although these features are the general aim of any radiotherapy treatment, normally, the term conformal radiotherapy is applied to treatment plans in which the target volumes are defined in three dimensions using contours drawn on many slices from a CT with multiple beam directions used to cross fire on the targets, and the individual beams are shaped to create a dose distribution that conforms to the target volume at desired dose levels. Radiation oncologist and medical physicist can avoid and mini-

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Table 1. ICRU report 50 target volume definitions (3) Abbreviation

Name

Description

GTV

Gross tumor volume

Volume of macroscopic tumor that is visualized on imaging studies

CTV

Clinical target volume

Volume that should be treated to a high dose, typically incorporating both GTV and volumes that are assumed to be at risk as a result of microscopic spread of the disease

PTV

Planning target volume

Volume that should be treated to ensure that the CTV is always treated, including considerations of systematic and random daily set-up errors and inter- and intratreatment motion

Figure 1. Three-dimensional conformal radiotherapy plan of a patient with breast cancer. Organs at risk and PTV doses are evaluated PTV: Planning target volume

mize the dose delivered to normal tissues by the correct definition of normal tissues. For ideal results, image guidance, accurate patient set-up, and immobilization for the management of motion and other changes to ensure accurate delivery of the planned dose distributions to the patient are required and very important for conformal treatment (2). 3D Conformal Radiotherapy The first conformal treatment planning technique based on the use of 3D treatment planning, multiple cross-firing with carefully shaped fixed fields is 3D conformal radiotherapy (3DCRT). For 3DCRT, preparatory aspects include positioning and immobilization of the patient in the treatment position at CT scan. Gross tumor volume (GTV), clinical target volume (CTV), organ at risk (OAR), and planning target volume (PTV) with daily set-up errors margin are defined with the images of 1 to 3 mm thick slices. Table 1 summarizes the target volumes described in detail in the International Commission on Radiation Units (ICRU) report 50 (3). A medical physicist makes a plan by using a treatment planning

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system to decide the type of energy, number of beams with their angles and directions, and collimator angle and to shape the target volume with multileaf collimators (MLCs). The dose received by the target and normal tissues is evaluated by dose volume histograms and isodose curves with protocols. Once the plan is approved, the set-up process is performed with matching planning and treatment imaging (Figure 1) (4). Intensity-Modulated Radiotherapy After the clinical practice of conformal radiotherapy, the idea of modulating intensity across each radiation beam in order to determine the shape of the target and surrounding organs assisted by computer-based optimization algorithm is determined (5, 6). Dividing the beam into numerous independent intensity beamlets allows for the modulation intensity of each beam of radiation so that each field can have multiple areas of high- and low-intensity radiation across the treatment area shaped with MLC and improved computer plan optimization called inverse

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Kandemir Gürsel Ö. Recent Technological Advances in Radiotherapy

planning. Conventional planning, in which the beam parameters are given first and the dose distributions are calculated, is “forward” planning. By contrast, intensity-modulated radiotherapy (IMRT) planning, in which the beam intensities are calculated to provide the given objectives and constraints on dose distributions to the target volume and OARs, is termed “inverse” planning (7). There are several studies with IMRT at head and neck, prostate, breast, lung, brain, gynecologic, and gastrointestinal cancers with less toxicities, sparing the adjacent organs nearby the target volume (8, 9). In a study, 3DCRT and IMRT plans for breast cancer were compared according to dose-volume histogram analyses in terms of PTV homogeneity and conformity indices as well as OARs dose and volume parameters. As a result, IMRT decreases the irradiated volumes of the heart and ipsilateral lung in high-dose areas while increasing irradiated volumes in low-dose areas in patients with breast cancer treated on the left side (10).

Figure 2. Target volume definition by the ICRU report 62 (16)

Figure 3. SRS of a patient with brain metastasis SRS: Stereotactic radiosurgery

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Volumetric Modulated Arc Therapy Volumetric modulated arc therapy (VMAT) is a new technique for increasing the efficiency of treatment in which a full 360° of beam directions for optimization with the entire dose volume is delivered in a single source rotation by regulating the dose rate and dynamic MLC as IMRT has increased treatment time by requiring a larger number of beam directions and increased monitor units (MU). The type of rotational system leads different levels of dose distributions to different parts of the tumor. VMAT can spare OAR better than IMRT with similar conformity and better homogeneity that leads to reducing time and MU that is important at uncomfortable immobilization, such as head and neck cancers (11, 12). VMAT and IMRT with the increase in low-dose radiation to the surrounding normal tissue could theoretically increase the risk of secondary malignancy compared with conventional techniques. In fact, the risk should be lower with VMAT, which uses fewer MU, than with conventional fixed field IMRT; this could be counteracted by the increase of normal tissue volume receiving low-dose wash. With highly efficient treatment delivery, VMAT is studied in many tumor types (13). Image-Guided Radiotherapy Image-guided radiotherapy (IGRT) is a companion to conformal radiotherapy that allows the treatment team to account for daily changes in target anatomy for positioning and setting up the patient by integrated megavoltage or kilovoltage diagnostic imaging, cone beam CT (CBCT), or radiographic fiducials (14). Cone beam CT (CBCT) takes projection radiographs with gantry rotation and helps to determine the correct target position before the RT fraction by registering volumetric image to the reference planning CT. Respiratory motion is a significant source of error in radiotherapy treatment planning for the thorax and upper abdomen sites. In a four-dimensional (4D) CT technique, there is a breathing motion in radiotherapy treatment planning, where multislice CT scans are collected simultaneously by digital spirometry over many free breathing cycles to create a 4D image set, and where tidal lung volume is the additional dimension (15). Internal target volume is defined by the ICRU report 62 as a volume for the internal movement of organs during radiotherapy (Figure 2) (16). There are different methods, such as breath-hold techniques, with either active, in which the airflow of the patient is temporarily blocked by a valve (active breathing control), or passive techniques by the patient’s voluntarily breath-hold gating; the radiotherapy beam synchronously with respiration to predict the phase of the respiration cycle while the patient breathes freely is called respiratory gating (17, 18). The future of IGRT is now MRI systems and linear accelerators for radiotherapy (MR-linacs), which defines a single device that can simultaneously produce diagnostic quality MRI images and deliver highly conformal IMRT-based treatments with better tumor visualization, online adaptation, and potential for image biomarker-based personalized RT (19). Adaptive Radiotherapy While radiotherapy course lasts several fractions and weeks to complete, there can be dosimetric variation at organs, patient weight loss, size and shape of the target as early tumor shrinkage, and change in OAR that causes difference at dose distribu-

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tion and treatment accuracy (20). The adaptive radiotherapy principle is used to measure variations during treatment and equalize planned dose distribution with final delivered dose distribution, with the help of image guidance, dose verification, and plan adaptation. This adaptation performs a decrease in late morbidity and an improvement in tumor control. Stereotactic Irradiation Stereotactic irradiation (STI) is an advanced radiotherapy method that converges multiple ionization radiation beams to the target from various directions, achieving high doses on the target and gradient dose falloff into the surrounding normal tissues. The word “stereotactic” means the target localized to a 3D coordinate system with either a rigid head frame or internal fiducial markers, such as bony landmarks or implanted markers. The optimal treatment delivery plan for STI has a high conformality that approaches the prescription dose at target volume while decreasing the high dose exposed to the normal tissue. Stereotactic irradiation (STI) is classified as stereotactic radiosurgery (SRS) using a single fraction and stereotactic body radiotherapy (SBRT) delivering treatment in a number of fractions (21-22). In the 1950s, SRS is initially termed as radiosurgery by Lars Leksell who designed the first unit working with a stereotactic frame and multiple hemispherical patterned cobalt-60 sources (23). In the 1980s, after linac advancements and modifications, linac-based robotic systems are adapted to stereotactic radiotherapy. It is indicated in intracranial lesions, such as brain metastases, meningiomas, acoustic neuromas, arteriovenous malformations, vestibular schwannomas, and pituitary tumors. Doses range from 12 to 20 Gy according to closure to the critical structures and the type of tumor (Figure 3) (24-26). Stereotactic body radiotherapy (SBRT) is an image-guided highdose radiotherapy for each 3-5 fraction at extracranial tumors. It has a process of patient immobilization, CT image acquisition, target delineation with the fusion of diagnostic images, dosimetric planning, quality assurance testing, guidance images for target relocalization, and real-time monitoring for the management of even breathing-related motion and patient stability. With SBRT, patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity (27). Prostate cancer, gastrointestinal cancer, and oligometastases are the other studied indications (28). Intraoperative Radiotherapy Intraoperative radiotherapy (IORT) is delivering radiation directly to the visualized tumor bed during surgery by exclusion of dose-limiting normal structures and significantly increasing dose with less morbidity. Doses differ on the extent of disease at resection to 10-20 Gy. The process is performed in the operating room with mobile X ray or electron beam devices with the help of applicators ranging in diameters. In malignancies with high local relapse rates, such as retroperitoneal sarcoma, gynecologic, pancreatic, and colorectal cancers, the addition of IORT to conventional treatment improved local control and survival (29). As local recurrences frequently occur at or near the adjacent tumor bed in breast cancers, IORT alone or with external beam radiotherapy can be an alternative for improved local control (30, 31).

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Brachytherapy Brachytherapy is an internal radiation therapy by placement of a radioactive source using applicators immediately adjacent to or within the tumor, providing a localized high dose of radiation. With the improvement of 3D imaging and conformal radiotherapy for optimizing the dose distribution, brachytherapy is an accurate and reliable treatment option for gynecologic cancers, prostate cancers, breast cancers, skin cancers, sarcomas, and ophthalmic diseases (32, 33). Proton Beam Radiotherapy Proton therapy is the most studied charged particle radiotherapy based on proton particles with recent major advances in particle accelerator technology that stops at a given depth depending on their initial energy (pristine Bragg peak), which allows to spare normal tissues distal to the tumor target from incidental irradiation. As the precision of methods for delivering photon therapy has improved over the past several decades, methods for planning and delivering proton therapy are evolving as well for treatment of tumors located nearby sensitive organs, such as ocular tumors, nasal tumors, skull-based tumors, and treatment of pediatric cases, where damage of the surrounding tissues can have severe consequences (34, 35). Hyperthermia Hyperthermia (HT) is an effective modality for the treatment of cancer by heating tumor tissues to temperatures ranging between 39°C and 45°C. The biological rationale for HT is reoxygenation, inhibiting the repair of sublethal and lethal damages and complementary cytotoxicity. Technological advances over the last decade in both hardware and software have led to potent and even safer locoregional HT treatment delivery, thermal treatment planning, thermal dose monitoring through non-invasive thermometry, and online adaptive temperature modulation. Combination with radiotherapy offers a unique immunomodulating prospect with superficial HT at skin, head and neck, and breast cancers and intracavitary HT for rectal cancer, esophageal cancer, and prostate carcinoma with substantial clinical benefits (36, 37).

Kandemir Gürsel Ö. Recent Technological Advances in Radiotherapy

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7. 8.

10.

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14.

CONCLUSION Technological advances with the integration of imaging and computer software in every phase of radiotherapy include simulation, MLC modulation of radiation beams, improved inverse treatment planning, image guidance, robotics, motion management strategies, and stereotactic treatments managed highly tailored dose distribution with maximum sparing of the surrounding structures, resulting in high tumor control rates and overall outcomes. Data from technology will progress in the future, and clinical studies of dose escalation, volume, fractionation, and avoidance of normal tissue lead to improving treatment response. Moreover, MRI- or PET-guided radiotherapy, targeted radiotherapy with nanoparticles, and combined immuno-radiotherapy treatments appeared to be the new future aspects.

15.

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20. Peer-review: Externally peer-reviewed. Conflict of Interest: The author has no conflicts of interest to declare. Financial Disclosure: The author declared that this study has received no financial support.

21.

Goitein M, Wittenberg J, Mendiondo M, Doucette J, Friedberg C, Ferrucci J, et al. The value of CT scanning in radiation therapy treatment planning. A prospective study. Int J Radiat Oncol Biol Phys 1979; 5: 1787-93. Gunderson LL, Willett GG. Clinical radiation oncology. In: Fraas B, Eisbruch A, Feng A. Intensity modulated and image guided radiation therapy. 4th edition. Philadelphia, Elsevier 2016: 294-324. ICRU Report 50: Prescribing, recording, and reporting photon beam therapy, Bethesda, MD, 1993, International Commission on Radiation Units and Measurements. Rosenman J, Sherouse GW, Fuchs H, Pizer SM, Skinner AL, Mosher C, et al. Three-dimensional display techniques in radiation therapy treatment planning. Int J Radiat Oncol Biol Phys 1989; 16: 263-9. Brahme A, Roos JE, Lax I. Solution of an integral equation encountered in rotation therapy. Phys Med Biol 1982; 27: 1221-9. Bortfeld T, Burkelbach J, Boesecke R, Schlegel W. Methods of image reconstruction from projections applied to conformation radiotherapy. Phys Med Biol 1990; 35: 1423-34. Cho B. Intensity-modulated radiation therapy: a review with a physics perspective. Radiat Oncol J 2018; 36: 1-10. Lee N, Puri DR, Blanco AI, Chao KS .Intensity-modulated radiation therapy in head and neck cancers: an update. Head Neck 2007; 29: 387-400. De Neve W, De Gersem W, Madani I .Rational use of intensity-modulated radiation therapy: the importance of clinical outcome. Semin Radiat Oncol 2012; 22: 40-9. Mansouri S, Naim A, Glaria L, Marsiglia H. Dosimetric evaluation of 3-D conformal and intensity-modulated radiotherapy for breast cancer after conservative surgery. Asian Pac J Cancer Prev 2014; 15: 4727-32. Otto K. Volumetric modulated arc therapy: IMRT in a single gantry arc. Med Phys 2008; 35: 310-7. Osborn J. Is VMAT beneficial for patients undergoing radiotherapy to the head and neck? Radiography 2017; 23: 73-6. Teoh M, Clark CH, Wood K, Whitaker S, Nisbet A. Volumetric modulated arc therapy: A review of current literature and clinical use in practice. Br J Radiol 2011; 84: 967-96. Moseley DJ, White EA, Wiltshire KL, Rosewall T, Sharpe MB, Siewerdsen JH. Comparison of localization performance with implanted fiducial markers and cone-beam computed tomography for on-line image-guided radiotherapy of the prostate. Int J Radiat Oncol Biol Phys 2007; 67: 942-53. Low DA, Nystrom M, Kalinin E, Parikh P, Dempsey JF, Bradley JD. A method for the reconstruction of four-dimensional synchronized CT scans acquired during free breathing. Med Phys 2003; 30: 1254-63. ICRU. Report 62: Prescribing, recording and reporting photon beam therapy (supplement to ICRU report 50). Bethesda: International Commission on Radiation Units and Measurements; 1999. Kubo HD, Hill BC. Respiration gated radiotherapy treatment: A technical study. Phys Med Biol 1996; 41: 83-91. Giraud P, Yorke E, Jiang S, Simon L, Rosenzweig K, Mageras G. Reduction of organ motion effects in IMRT and conformal 3D radiation delivery by using gating and tracking techniques. Cancer Radiother 2006; 10: 269-82. Pollard JM, Wen Z, Sadagopan R, Wang J, Ibbott GS. The future of image-guided radiotherapy will be MR guided. Br J Radiol 2017; 90: DOI: 10.1259/bjr.20160667. Yan D. Adaptive radiotherapy: merging principle into clinical practice. Semin Radiat Oncol 2010; 20: 79-83. Solberg TD, Balter JM, Benedict SH, Fraass BA, Kavanagh B, Miyamoto C, et al. Quality and safety considerations in stereotactic radiosurgery and stereotactic body radiation therapy: Executive summary. Pract Radiat Oncol. 2012; 2: 2-9.

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22. Barnett GH, Linskey ME, Adler JR, Cozzens JW, Friedman WA, Heilbrun MP, et al. Stereotactic radiosurgery-an organized neurosurgery-sanctioned definition. J Neurosurg 2007; 106: 1-5. 23. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 1951; 102: 316-9. 24. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665-72. 25. Santacroce A, Walier M, Régis J, Liščák R, Motti E, Lindquist C, et al. Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurg 2012; 70: 32-9. 26. Soliman H, Das S, Larson DA, Sahgal A. Stereotactic radiosurgery (SRS) in the modern management of patient with brain metastases. Oncotarget 2016; 7: 12318-30. 27. Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010; 303: 1070-6. 28. Kavanagh BD, McGarry RC, Timmerman RD. Extracranial radiosurgery (stereotactic body radiation therapy) for oligometastases. Semin Radiat Oncol 2006; 16: 77-84. 29. Pilar A, Gupta M, Ghosh Laskar S, Laskar S. Intraoperative radiotherapy: review of techniques and results. Ecancermedicalscience 2017; 11: 750. 30. Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al. Intraoperative radiotherapy versus external radio-

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therapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol 2013; 14: 1269-77. Fastner G, Sedlmayer F, Merz F, Deutschmann H, Reitsamer R, Menzel C, et al. IORT with electrons as boost strategy during breast conserving therapy in limited stage breast cancer: long term results of an ISIORT pooled analysis. Radiother Oncol 2013; 108: 279-86. Thomadsen BR, Erickson BA, Eifel PJ, Hsu IC, Patel RR, Petereit DG, et al. A review of safety, quality management, and practice guidelines for high-dose-rate brachytherapy: executive summary. Pract Radiat Oncol 2014; 4: 65-70. Nag S. High dose rate brachytherapy: its clinical applications and treatment guidelines. Technol Cancer Res Treat 2004; 3: 269-87. Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014; 89: 292-302. Doyen J, Bondiau PY, Benezery K, Thariat J, Vidal M, Gérard A, et al. Indications and results for protontherapy in cancer treatments. Cancer Radiother 2016; 20: 513-8. Triantopoulou S, Efstathopoulos E, Platoni K, Uzunoglou N, Kelekis N, Kouloulias V. Radiotherapy in conjunction with superficial and intracavitary hyperthermia for the treatment of solid tumors: survival and thermal parameters. Clin Transl Oncol. 2013 Feb;15(2):95105 Datta NR, Ordó-ez SG, Gaipl US, Paulides MM, Crezee H, Gellermann J et al. Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. Cancer Treat Rev 2015; 41: 742-53.

Review

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Effects of Technological Innovations on Reconstructive Microsurgery; Flap Monitoring Systems After Free Tissue Transfer, Yesterday and Today Özlem Çolak1

, Özay Özkaya Mutlu2

, Kadri Özer3

Department of Plastic Surgery, University of Health Sciences, Okmeydanı Training and Research Hospital, İstanbul, Turkey 2 Private Practice, İstanbul, Turkey 3 Department of Plastic Surgery, Aydın State Hospital, Aydın, Turkey 1

Abstract

ORCID IDs of the authors: Ö.Ç. 0000-0002-0201-1649; Ö.Ö.M. 0000-0001-6316-2347; K.Ö. 0000-0003-2966-6618 Cite this article as: Çolak Ö, Özkaya Mutlu Ö, Özer K. Effects of Technological Innovations on Reconstructive Microsurgery; Flap Monitoring Systems After Free Tissue Transfer, Yesterday and Today. Eur Arch Med Res 2018; 34 (Suppl. 1): S61-S65. Corresponding Author: Özlem Çolak E-mail: drozlemcolak@hotmail.com Received: 05.11.2018 Accepted: 13.11.2018 DOI: 10.5152/eamr.2018.59244 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Microvascular anastomoses for the transfer of viable tissue are the basis of reconstructive surgery, and they are used to treat a broad spectrum of clinical problems. Recent advances in technology are promising in the improvement of microsurgery outcomes. The primary threat in reconstructive surgery is anastomotic vascular thrombosis, which can lead to tissue loss with potentially destructive consequences. Postoperative monitoring of tissue perfusion is critical because early recognition of vascular compromise and a rapid surgical intervention are associated with tissue recovery. Conventional flap monitoring methods used to be the primary means of monitoring during postoperative follow-up, but they were highly subjective and observer dependent. Medical devices introduced in flap monitoring have eliminated many of these shortcomings and have greatly improved this critical stage of reconstructive surgery. Although the features of the ideal monitoring device have been defined, there is no existing device that could meet all the currently expected requirements. In the near future, we are more likely to see further enhancement and clinical applications of existing technologies. Keywords: Reconstructive surgery, microsurgery, flap monitoring, technology

INTRODUCTION Free flap was first introduced in the late 1950s, and it became a widely used tool in the reconstruction of large defects, with a success rate of up to 95% after the development of microsurgical techniques (1-4). Many etiologies, including cancer, trauma, infection, and congenital defects, may lead to microvascular reconstruction (5). For example, an amputated finger can be rescued only when the blood supply is restored by performing microvascular anastomoses in trauma patients who are admitted to our clinic and operated on after their informed consent forms are received (Figure 1). When the mastectomy is performed in women with breast cancer after obtaining their consent, the abdominal tissue is usually transferred to regenerate the breast (Figure 2). This technique has recently been used for tissue transfers such as facial and hand allotransplantation between different individuals (6, 7). Along with the development of auxiliary flap monitoring techniques, the success rates, including a lower number of complications, increased efficiency, a shorter hospital stay, and improved overall results, have increased (8). This article summarizes current literature that supports the devices and protocols that are routinely used for postoperative free flap monitoring techniques and are planned to be used in the future. Flap Monitoring The primary threat to reconstructive surgery is vascular thrombosis, which may occur in the anastomosis line due to some characteristics of the recipient. If surgery is not performed, tissue loss

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accompanied by devastating consequences may occur. Since an early diagnosis of the vascular problem and the surgical intervention are closely related to the tissue recovery, postoperative monitoring of the perfusion of the transplanted tissue is extremely important.

Figure 1. Restoration of blood flow after fingertip amputation and replantation in a trauma patient

Conventional flap monitoring methods include the clinical evaluation of the skin color, capillary filling, turgor, and flap temperature; however, these values are highly subjective and are observant dependent. The use of assistive technologies for flap perfusion and monitoring can provide early detection of possible complications. In 1975, Creech and Miller described the features of an ideal monitoring device as safe, fast, sensitive, reliable, and applicable to all flap types (9). In addition, the features that are expected from an ideal device are cost efficiency, ease of use, and continuous monitoring. While all these criteria appear to be reasonable, there are no existing devices that currently meet all these requirements.

Figure 2. a-d. Microvascular breast reconstruction; (a) Planning of microvascular free tissue transfer from the abdomen in a patient undergoing mastectomy for left-side breast cancer; (b) Preparation of the abdominal tissue for transfer; (c) Vessels in which microvascular anastomosis will be performed for the transplantation of the abdominal tissue; (d) Postoperative image

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icle or from the recipient vessels, and the lack of quantitative measurement. Color Duplex Ultrasonography Color duplex ultrasound is a noninvasive flap monitoring technique that uses ultrasound to visualize microanastomosis vessels. The device consists of an ultrasound probe and a monitor that can be used in the radiology chamber or can be transported to the patient room. The person using the device first uses grayscale ultrasound to identify the static structures in the environment, such as postoperative fluid, and the vessels that have newly been anastomosed. Since the shift of ultrasound waves in the Doppler is in the audible range, and since different tones are assigned to different rates on the color scale, the flow through the anastomosis is visually noticeable (11). Often, the red color tints are used to indicate the current flowing toward the probe, and the blue color tints are used to indicate the current moving away from the probe. The use of this device requires a trained radiology technician, and a microsurgeon to assist with anatomical orientation, in addition to clinical radiologist. Figure 3. Hand Doppler Flap monitoring techniques can be classified according to the monitoring mechanism (vascular flow measurement according to tissue ischemia); time of use (intraoperative and postoperative); and invasiveness (invasive and noninvasive). The techniques monitoring the vascular flow include hand Doppler, implantable Doppler, color duplex ultrasonography, fluorescence angiography, and laser Doppler flowmeter (LDF). The techniques monitoring the tissue metabolism and ischemia are near-infrared spectroscopy and microdialysis. There are additional developing techniques such as thermal imaging, pH monitoring, transit-time volume flow measurement, and spatial frequency domain imaging (SFDI). Hand Doppler Acoustic Doppler sonography is the most commonly used method for free flap monitoring. Typically, it is used in accordance with physical examination. The most common type of this device is the one that is handheld, and it is connected with a probe to a central component containing the power and sound source (Figure 3). Handheld Doppler with a low-frequency continuous 8 mHz wavelength probe, which was first described by Karkowski and Buncke as a postoperative monitoring technique, is used to qualitatively determine the vascular flow (10). Since the distribution of arteries and vessels within the flap is not uniform, the probe is often applied to the flap surface before the surgery is completed, and the signal locations are then marked for postoperative monitoring. It is important to know that these surface signals generally represent the blood flow through smaller and more peripheral blood vessels close to the surface of the flap, but not the blood flow through the vessels involved in the microvascular anastomosis, which are generally embedded in the flap and cannot be accurately evaluated. It is also important that they cannot be evaluated with these handheld probes. The advantages of hand Doppler include ease of use, noninvasiveness, and reusability. Its disadvantages are the difficulty in determining whether the signal source is from the vascular ped-

The advantages of the device are that it is noninvasive, it can directly visualize the precise and quantitative characterization of in and outflow from the anastomotic openings of both vessels, and it can also be used in embedded flaps. Its disadvantage is that an experienced ultrasound technician or radiologist is needed to use the device. Implantable Doppler This device allows continuous monitoring of free flaps by applying the Doppler principle to an area adjacent to the microvascular anastomosis. It was first described by Swartz et al. in 1988, and little change has been made in its design so far (12). Implantable Doppler uses a 1 mm2 piezoelectric crystal that acts as a 20 MHz ultrasonic Doppler probe. The probe is mounted on a 0.5-cm-wide silicone cuff, which is applied circumferentially around a blood vessel immediately distal to an anastomosis. The cuff is then secured to the two ends of the blood vessel using any of the variety of methods, including surgical clips, sutures, or fibrin glue (13). The probe and the cuff are connected to an audio and power source producing an audible signal through a wire coming out from the surgical incision and transmitting the Doppler signal. Once the postoperative monitoring is complete, the crystal and wire are easily separated from the cuff. The implantable Doppler can be applied to the artery, vein, or both if two devices are to be used. Many surgeons prefer to keep the device in venous anastomosis where both arterial and venous problems are more evident, rather than in arterial anastomosis where venous problems cannot be detected. The ability to make continuous measurements, ease of use, and the availability of embedded flaps are among the advantages of the device. The fact that it lacks quantitative measurement and that it is an invasive technique despite relatively simple mounting and removal are among the disadvantages. Fluorescence Angiography Infrared fluorescence angiography has recently been developed for the clinical use in microsurgery. The indocyanine green, a non-toxic dye, is injected into the vessel and circulated through the vascular system. It is then illuminated with laser that can be captured by a near-infrared camcorder, causing the stimulation

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of the dye in the vascular system of the related tissue and then an infrared energy emission. A real time video visualization of the vascular flow is displayed on a monitor. Fluorescence angiography samples include the fluorescence-assisted resection and exploration (FLARE) imaging system (Curadel, Marlborough, MA) and the SPY fluorescence imaging system (Stryker, Kalamazoo, MI) (Figure 4) (14,15). Smaller systems such as PDE Neo (Mitaka, Denver, CO) have been developed. The advantages of fluorescent angiography include direct visualization of vascular flow and tissue perfusion. An instant data capture, a high cost of the device, and a relative contraindication in patients with iodine allergy and renal failure are among the disadvantages. In addition, although frequent use is possible, the large size and cost of the device limit the bedside use of the monitor postoperatively. Laser Doppler Flowmeter The reflection of coherent laser light in Doppler is used to measure the blood flow velocity in LDF. The laser light is emitted from a source, and the back-scattered light, through which the frequency shift is determined, is collected. This frequency shift is proportional to the number and speed of the red blood cells in the measured area. The measurements are expressed as relative velocities, usually in the form of mL/min/100 g, which are the abbreviated LDF units (16,17). It is a noninvasive and continuous imaging device that evaluates perfusion and shows the flow within the tissue capillaries rather than pedicles. Periflux System 5000

Figure 4. SPY fluorescence imaging system

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(Perimed, Kings Park, NY) and O2C (Oxygen to See, LEA Medizintechnik, Giessen, Germany) are the examples of this technology. It was first described in 1977 by Stern et al. to assess skin perfusion (18). Early device configurations included LDFs that were physically connected to a separate personal computer to automatically and continuously record data. Existing device models for flap monitoring have concentrated the data-processing component into a much smaller portable unit. The probes are applied to the flap surface and radiate the laser light to a depth of 8 mm (19). The reflected light is collected by the same probe, and the frequency shift between the transmitted and the reflected light is calculated to display a numerical flow value (20). The advantages of the device are that it provides a continuous monitoring, it is noninvasive, and it allows the recognition of possible flap failures prior to clinical findings. In contrast to other devices, it has various probes that can be applied to various types of tissues, including skin, muscle, and internal organ flaps. A high cost, the inability to discriminate arterial and venous pathology, sensitivity to small movements, relative value reporting, and the lack of a critical threshold to demonstrate the flap failure are among the disadvantages. Near-Infrared Spectroscopy In this technique, a source emits the light of a given wavelength toward an object, and a detector measures the decrease in light intensity and scattering. Based on the characteristic absorption spectrum, the concentration of a particular chromophore can be determined. The spectroscopic devices used for free flap monitoring generally use near-infrared light (650-900 nm) that can penetrate to a depth of 20 mm with a light source and a detector located within a single probe. The probe is easily applied and fixed using an adhesive wrap or suture (21). The chromophores of light spectrum in human tissues for this region are deoxygenated (Hb) and oxygenated hemoglobin (HbO2) (22). The sum and rate of these two measurements can be used to calculate the relative changes in the total hemoglobin concentration and oxygen saturation (StO2), the two most commonly reported values by tissue spectrometry devices. ViOptix T.Ox (ViOptix, Newark, CA) is among the commercial examples of near-infrared spectroscopy. The advantages of the device are that it provides a continuous monitoring, it is noninvasive, it is less sensitive to motion (different from a LDF), and it allows the detection of the possible flap failures before the clinical findings. Its disadvantages are that it has a high cost, it cannot distinguish between an arterial and venous pathology, and it reports the relative values rather than the absolute ones. Microdialysis Microdialysis, used for the first time in 1998 by RĂśjdmark et al. in flap monitoring, is an invasive technique that allows intermittent flap monitoring (23). A regional blood flow disorder causes a decrease in tissue oxygen, which requires transition to anaerobic metabolism. Thus, an increase in the concentration of anaerobic metabolic products indicates local hypoperfusion and ischemia. Microdialysis evaluates the concentration of these products in the regional tissue with the dialysis membrane placed in the subcutaneous, adipose, or intramuscular tissue of the flap by inserting a sterile double-lumen microdialysis catheter. The physiological fluid delivered through the catheter along the dialysis membrane is balanced by the interstitial fluid surrounding the catheter on either side of the membrane. Thus, the collected liquid sample

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reflects the composition of the interstitial fluid and the tissue concentration of metabolites, such as glucose, lactate, and pyruvate, which are shown numerically and graphically via a monitor, can be analyzed at the bedside. Ischemia is characterized by low glucose, high lactate, an increased lactate/pyruvate ratio, and high glycerol. The fact that it can be used in embedded flaps can be considered among the advantages. To improve free flap reliability and flap monitoring, the interest in innovations and technology is increasing every day. Although high-resolution thermal imaging cameras are often quite expensive, the newly developed FLIR ONE (FLIR Systems, Inc., Wilsonville, OR) is a lower-resolution, smartphone-compatible miniature thermal camera with less than $200. Similar to microdialysis, pH monitoring also permits an increase in hydrogen ion concentration, indications of regional anaerobic metabolism developing secondary to flap ischemia, and thus a mediator for vascular compromise. Transit-time volume flow measurement is a non-Doppler-based ultrasound technology that does not provide a continuous display, that detects physiological parameters of blood vessels and particularly vascular flow and resistance, and that improves cardiac surgery results when previously used to assess the coronary artery bypass quality. Finally, the SFDI is a new, infrared, and wide-field imaging technology with a mechanism similar to FLARE, but it is noninvasive and does not require dye injection. Although these devices equipped with new technological developments have a limited clinical use, they are commercially under development.

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6. 7. 8. 9. 10.

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CONCLUSION Traditional monitoring methods are cheap, accurate, and easy to follow. However, the implantable Doppler system, LDF, and near-infrared spectroscopy are continuous methods that have been reported to detect the flap failure earlier than traditional methods and that appear to be the best monitoring techniques for most types of flaps currently. In addition, implantable Doppler and microdialysis techniques have been shown to be used successfully in embedded flaps. In the near future, there is a high likelihood of further development of existing technologies and their clinical applications. For example, new products that combine two existing technologies (such as spectroscopy and LDF) and that transmit devices with additional data sources (such as heat, acoustic Doppler) to mobile devices in real time will be developed.

Peer-review: Externally peer-reviewed. Author Contributions: Concept - Ö.Ö., Ö.Ç.; Design - Ö.Ç., K.Ö.; Supervision - Ö.Ö., K.Ö.; Resources - K.Ö., Ö.Ç.; Data Collection and/or Processing - Ö.Ç., K.Ö., Ö.Ö.; Literature Search - K.Ö., Ö.Ç.; Writing Manuscript - Ö.Ç., K.Ö., Ö.Ö.; Critical Review - Ö.Ö., K.Ö. Conflict of Interest: The authors have no conflicts of interest to declare. Financial Disclosure: The authors declared that this study has received no financial support.

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Nakatsuka T, Harii K, Asato H, Takushima A, Ebihara S, Kimata Y, et al. Analytic review of 2372 free flap transfers for head and neck reconstruction following cancer resection. J Reconstr Microsurg 2003; 19: 363-8. Smit JM, Acosta R, Zeebregts CJ, Liss AG, Anniko M, Hartman EH. Early reintervention of compromised free flaps improves success rate. Microsurgery 2007; 27: 612-6. Jones NF, Jarrahy R, Song JI, Kaufman MR, Markowitz B. Postoperative medical complications-not micro-surgical complications-negatively influence the morbidity, mortality, and true costs after microsurgical reconstruction for head and neck cancer. Plast Reconstr Surg 2007; 119: 2053-60. Chao AH, Meyerson J, Podovski SP, Kocak E. A review of devices used in the monitoring of microvascular free tissue transfer. Expert Rev Med Devices 2013; 10; 649-60. Siemionow M, Ozturk C. An update on facial transplantation cases performed between 2005 and 2010. Plast Reconstr Surg 2011; 128: 707-20. Shores JT, Imbriglia JE, Lee WP. The current state of hand transplantation. J Hand Surg Am 2011; 36: 1862-7. Karinja SJ, Lee BT. Advances in flap monitoring and impact of enhanced recovery protocols. J Surg Oncol 2018; 1-10. Ferguson RE Jr, Yu P. Techniques of monitoring buried fasciocutaneous free flaps. Plast Reconstr Surg 2009; 123: 525-32. Karkowski J, Buncke HJ. A simplified technique for free transfer of groin flaps, by use of a Doppler probe. Plast Reconstr Surg 1975; 55: 682-6. Stone CA, Dubbins PA, Morris RJ. Use of colour duplex Doppler imaging in the postoperative assessment of buried free flaps. Microsurgery 2001; 21: 223-7. Swartz WM, Jones NF, Cherup L, Klein A. Direct monitoring of microvascular anastomoses with the 20-MHz ultrasonic Doppler probe: an experimental and clinical study. Plast Reconstr Surg 1988; 81: 149-61. Smit JM, Werker PM, Liss AG, Enajat M, de Bock GH, Audolfsson T, et al. Introduction of the implantable Doppler system did not lead to an increased salvage rate of compromised flaps: a multivariate analysis. Plast Reconstr Surg 2010; 125: 1710-7. Lee BT, Matsui A, Hutteman M, Lin SJ, Winer JH, Laurence RG, et al. Intraoperative near-infrared fluorescence imaging in perforator flap reconstruction: current research and early clinical experience. J Reconstr Microsurg 2010; 26: 59-65. Lee BT, Hutteman M, Gioux S, Stockdale A, Lin SJ, Ngo LH, et al. The FLARE intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in perforator flap breast reconstruction. Plast Reconstr Surg 2010; 126: 1472-81. Clinton MS, Sepka RS, Bristol D, Pederson WC, Barwick WJ, Serafin D, et al. Establishment of normal ranges of laser Doppler blood flow in autologous tissue transplants. Plast Reconstr Surg 1991; 87: 299-309. Heller L, Levin LS, Klitzman B. Laser Doppler flowmeter monitoring of free-tissue transfers: blood flow in normal and complicated cases. Plast Reconstr Surg 2001; 107: 1739-45. Stern MD, Lappe DL, Bowen PD, Chimosky JE, Holloway GA Jr, Keiser HR, et al. Continuous measurement of tissue blood flow by laser-Doppler spectroscopy. Am J Physiol 1977; 232: 441-8. Hallock GG. Acoustic Doppler sonography, color duplex ultrasound, and laser Doppler flowmetry as tools for successful autologous breast reconstruction. Clin Plast Surg 2011; 38: 203-11. Bonner R, Nossal R. Model for laser Doppler measurements of blood flow in tissue. Appl Opt 1981; 20: 2097-107. Colwell AS, Craft RO. Near-infrared spectroscopy in autologous breast reconstruction. Clin Plast Surg 2011; 38: 301-7. Xu RX, Young DC, Mao JJ, Povoski SP. A prospective pilot clinical trial evaluating the utility of a dynamic near-infrared imaging device for characterizing suspicious breast lesions. Breast Cancer Res 2007; 9: 88.

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A New Era Has Begun in Neurology Thanks to Gene and Biotechnologies Cihat Örken Department of Neurology, University of Health Sciences, Okmeydanı Training and Reserch Hospital, İstanbul, Turkey

Abstract Human genetics has evolved considerably since the discovery of DNA. New gene- and biotechnologies invented for the last three decades have inspired novel treatments for diseases that were once accepted as untreatable. Congenital neuromuscular disorders and neurodegenerative diseases are typical examples of these diseases. Novel emerging trials demonstrate promising results to alter the poor prognosis of these unfortunate patients. Keywords: Genetics, neurogenetics, gene technologies, biotechnology, gene therapy

INTRODUCTION Human genetics has covered remarkable advances over the last three decades to be merited as a genetic revolution. Actually, this advancement has been achieved in conjunction with tremendous progress in the field of molecular biology. The first identification of human disease-associated genes in the 1980s and the sequencing of whole human genome in 2001 were two major steps in this development. These advances stimulate hope-inspiring approaches for the practice of medicine in general and the practice of neurology in particular. The leap in the field is great, so the main theme of the 4th Congress of the European Academy of Neurology in 2018 was neurogenetics (1). ORCID ID of the author: C.Ö. 0000-0002-7998-0843 Cite this article as: Örken C. A New Era Has Begun in Neurology Thanks to Gene and Biotechnologies. Eur Arch Med Res 2018; 34 (Suppl. 1): S66-S70. Corresponding Author: Cihat Örken E-mail: cihat.orken@gmail.com Received: 18.09.2018 Accepted: 24.10.2018 DOI: 10.5152/eamr.2018.46855 Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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Advances in Gene- and Biotechnologies In 1953, the genetics era started with the discovery of the double helix DNA. In 1983, polymerase chain reaction was discovered and entirely modified DNA studies. Molecular analysis of mammalian genes has changed greatly ever since. In 1977, Sanger published an article about his DNA sequencing method. Sanger‘s approach widely spread across the research community and finally integrated into clinical diagnostics. The sequencing of the first human genome-Human Genome Project-was accomplished by using the Sanger method. The sequencing lasted 13 years and was completed in 2001, with an estimated cost of $2.7 billion. In 2008, the time needed to sequence human genome declined to 5 months, and the cost decreased to $1.5 million. Today, the sequencing can be performed in a couple of days with a cost of $10,000. In 2005, the launch of the first massively parallel pyrosequencing platform for commercial use made the subsequent progress possible. This led to high-throughput genomic analysis now referred to as next-generation sequencing (NGS). NGS platforms share a common technological feature, namely, massively parallel sequencing of clonally amplified or single DNA molecules. This design is much faster than Sanger sequencing and surveys high numbers of specimen. It is expected that the time and cost will decrease more in the very near future, making these technologies affordable for more researchers (2). Table 1 summarizes the major milestones in gene- and biotechnologies. Technologies for Gene Therapy Gene therapy is designed to introduce the genetic material into the cells to repair abnormal genes. If a mutated gene damages an essential protein, the functionality of that protein may recover through gene therapy. Gene therapy can be successful by refinement of gene delivery

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Örken C. New Technologies for Neurological Diseases

1953

Discovery of the DNA double helix

can mediate only gene addition. Multiple clinical genome editing trials aiming to integrate these new technologies to patient care are ongoing (4).

1983

Discovery of PCR- changing the DNA study method

Table 2 outlines the current technologies for gene therapy.

1977

Sanger’s DNA sequencing method (technology)

1994 1998

Emerging of Massive parallel sequencing (MPS) - high throughput approach to DNA sequencing.

2001

Sequencing of the first human genome

2002

First successful GWAS (about myocardial infarction) was published

2005

Commercialising of MPS - Next generation sequencing

2007

Array- based hybrid capture method: target enrichment strategy to be applied to whole exome sequencing

2011

Third generation sequencing Cheaper and faster sequencing of human genome

Gene- and Biotechnologies in Neurology In 1986, the identification of the Duchenne muscular dystrophy (DMD) gene was the first for neurological disorders. Others followed in rapid succession. Disease-associated genes have been discovered perpetually. As a consequence, genetic testing should be integrated into clinical practice. In 1995, barely 10 commercially available tests relevant to neurology were available. Now, there are several hundred tests to all areas of clinical neurology, including neuromuscular disorders, dementias, movement disorders, strokes, and white matter diseases. Comprehensive open sources for these tests are being updated regularly. For instance, Gene Reviews currently comprises 721 chapters focused on a single gene or phenotype. There are also overviews summarizing the genetic causes of common conditions, such as Alzheimer’s disease (5).

Table 1. Milestones in gene technologies

Table 2. Technologies for gene therapy Virus mediated gene therapy

Viruses capable of invading selected tissues deliver desired gene to target cell populations and induce long-term expression

Short synthetic nucleotids

Antisense oligonucleotids (ASO) and RNA interference (RNAi) modify disease proteins by targeting RNA/DNA precursors

Genomic DNA editing / engineering

Uses the CRISPS/CAS9 system to remove sections of malfunctioning (mutated) genomic DNA and replace these with normal sequences

Polymer encapsulated cell technology

Convection-enhanced delivery technique

A nonviral approach -uses a semipermeable membrane that allows free exchange of nutrients, oxygen and therapeutic gene products while shielding the implanted cells from host immune system and preventing uncontrolled cellular proliferation and mass formation circumvents the BBB in delivering agents directly into the brain

systems. Researchers have been concentrating on nonviral and viral gene transfer vectors. Various physical and chemical nonviral methods exist to introduce DNA and mRNA to mammalian cells. Much of these methods have been developed for gene therapy procedures. Viruses are the most eligible vectors for the delivery of therapeutic agents, and significant numbers of clinical trials employ this technology. Adenoviruses (Ads) are the most commonly researched viral vectors. Recombinant adeno-associated virus (AAV) vector-mediated gene therapy has demonstrated to be effective in certain conditions (3). In recent years, genome editing technologies have been developed based on engineered or bacterial nucleases. Genome editing methods provide opportunities for gene addition, gene ablation, and gene correction in contrast to viral vectors that

New Perspectives in Neurology in the Context of Gene- and Biotechnologies More genes are being discovered constantly relevant to neurological disorders. As a consequence, new options are revealed day by day in diagnosing and treating these disorders. This is becoming truer as the use of clinical exome and genome sequencing becomes increasingly widespread. Technological advancements pave the way for the genomic medicine era. Clinicians are now faced with the problem of associating this new genetic information with daily clinical practice (6). New genetic and molecular biology information has promoted new approaches in diagnosis, genetic counseling, prognosis, and treatment. Evaluation and Diagnosis The vast number of genetic testing available for single gene disorders and for genomic variation makes the evaluation and diagnosis increasingly easier. Many commercial laboratories provide tests for Mendelian disease genes, and in some instances, genetic testing has been routinely used similar to other common blood tests (7). For instance, in a Germanybased laboratory with a large panel approach, 351 genes that are associated with hereditary neurodegenerative diseases are sequenced by NGS. Twenty-nine sets of genes are engaged due to main disease types. For example, they can scan 40 genes for the diagnosis of dystonia. Using a large panel approach, this laboratory revealed that its sensitivity and specificity are 99.7% and 99.9%, respectively, in diagnosis (8). Clinical examination is a prerequisite to define the patient’s phenotype, which will in turn propose the most proper conditions for genetic testing. As bio- and gene technologies proceed, the secrets of human genetic variation are increasingly revealed as well. Therefore, it is easier to associate these findings to clinical phenotype nowadays. Traditionally, in single gene (Mendelian) disorders, patients were assumed to be either healthy or diseased depending on their genetic condition. Friedreich ataxia (FA) or Huntington disease is an example of Mendelian disorder. However, common neurodegenerative dis-

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Table 3. Gene therapy trials for neurological disorders Alzheimer’s disease

Immunotherapy Vaccine Neurotrophic factors Anti-inflammation

Aß antibody Aß cDNA IGF2 IL-4

Decreased Aß deposition in AD mouse models Decreased Aß deposition, improved memory and cognition ability Promoted dendritic spine formation, restored normal hippocampal excitatory synaptic transmission in AD mouse model Reduced astro-/microgliosis, enhanced neurogenesis, improved spatial learning in AD mouse model

Parkinson’s disease

Dopamine biosynthesis enzyme STN activity modulation Neurotrophic factors

AADC GAD NTN

AAV2-AADC delivery into putamen alleviated motor symptoms in moderate and advanced PD patients Stable and persistent transgene expression Bilateral delivery of AAV2-GAD65/67 into STN of advanced PD patients provide modest improvement İntraputaminal injection of CERE-120 (AAV2-NTN) resulted in improvement in motor function

Spinal muscular atrophy

Stimulate SMN2 exon 7 to SMN1 increase SMN protein concentrations

Nusinersen has recently been licenced for treatment for SMN

Duchenne muscular distrophy

Skipping of exons to correct reading frame disruptions using antisense oligonucleotides (ASO)

Dystrophin

Antisense oligonucleotide Eteplirsen reduce the severity of DMD and produce a milder phenotype

Familial amyloid polyneuropathy

Degradation of thransthyretin mRNA

Transthyretin (TTR)

Antisense oligonucleotide inotersen and RNAi patisiran both completed phase III clinical trials. Aim is to deplete total TTR levels to restrict amyloid deposition

Friedreich ataksia

Restoring wild-type gene expression levels and reversing cellular transcription changes

Frataxine

Correction of changes induced by frataxin downregulation, sustained elevation of frataxin mRNA and protein a phase I study to increase frataxin levels in peripheral blood mononuclear cells

Fabry disease

Recombinant enzyme replacement Increasing GLA activity

Alphagalactosidase A (GLA)

Agalsidase alfa (Fabrazyme) decreases globotriaosylceramide (GL-3) accumulation, was approved by FDA in 2003.

Pompe disease

Recombinant enzyme replacement

Acid α-glucosidase

Myozyme enabled all patients to live to the age of 18 months, a 99% reduction in death, was approved by FDA in 2006

Huntington’s disease

Mutant HTT Knockdown Neurotrophic factors

shRNA siRNA GDNF CNTF

Reduced brain atrophy, rescue of motor deficits and increase in survival in HD mouse model Complete elimination of mutant HTT-positive inclusions with improved behavioural deficits in HD mouse model Improved motor function and increased striatal neuron survival Transplantation of polymer-encapsulated BHK cells secreting CNTF into the lateral ventricles of HD patients improved electrophysiologically

Amyotrophic lateral sclerosis

Mutant SOD1 Knockdown Nonsense mediated mRNA decay Neurotrophic factors

shRNA UPF1 GDNF VEGF

Delayed disease onset, enhanced survival of spinal motor neurons, expanded lifespan in ALS SOD1 rat model Preservation of forelimb function and improved motor scores in ALS TDP43 rat model İntramuscular injection of AAV-GDNF delayed disease onset and prolonged survival in ALS mouse model Ex vivo delivery of GDNF andVEGF showed synergistic effect in ALS SOD mouse model

Stroke

Anti-ischemia induced apoptosis Anti-inflammation Neurotrophic factor Blocking BBB disruption Prevention of vasospasm

Bcl-2 and Bcl-w IL-1 sTNFR1 BDNF MMP-9 shRNA CGRP eNOS

Delayed ischemia neuronal death, reduction in infarct size and improvement in neurological function Reduced cerebral infarct volume Smaller infarct size and decreased inflammation Intrastriatal delivery of rAAV-NGF and BDNF can lessen neuronal death and save function after middle cerebral artery occlusion in rat model İmproved ischemic brain injury Ameliorated ischemic brain injury Reduced vasospasm, partly restored vasodilator response in canine model

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orders, such as Alzheimer disease (AD) and Parkinson’s disease (PD) in particular, and more common neurological diseases, such as epilepsy and stroke, might stem from the interaction of multiple genes. Each of these genes might play distinctive roles in disease susceptibility and conceivably interact with environmental factors (7). Genetic susceptibility factors-a variety of genes and biomarkers that present a risk of illness-have been identified in a fast pace. For instance, many biomarkers, such as amyloid beta (Aβ) (1-42), total tau, and phosphorylated tau 181 in the cerebrospinal fluid, were described that are currently being used as surrogate markers for presymptomatic AD. Many studies are currently in the pipeline to discover dependable blood biomarkers for AD (9). Genome and/or exome sequencing tests are being integrated into clinical practice gradually. The cost would decrease to that of a magnetic resonance imaging study within 5 years (10). Prognosis and Treatment A diagnosis can be helpful to predict the prognosis. It may also warn the clinician about potential life-threatening comorbidities, such as cardiomyopathy in FA. Currently, the majority of genetic diseases are incurable. However, while symptomatic relief and even prevention of disease progression could be achieved for many of them, genetic etiology in these cases should be identified as soon as possible. Phenylketonuria is an excellent example of this, since dietary restriction of phenylalanine initiated soon after birth will prevent cognitive impairment and enable virtually normal development (11). Treatment in the Biotechnology Era Translational medicine aims to integrate new information about disease pathology at the molecular level to clinical practice-treatment in particular. Recent new treatments, which take advantage of the molecular aspects of these disorders, show promise in the clinic. Even some have been licensed and showed results unimaginable previously. Some outstanding and dramatic examples will be discussed below.

Örken C. New Technologies for Neurological Diseases

fies pre-messenger RNA splicing of the SMN2 gene-promotes the increased production of full-length SMN protein that is deficient in SMA (14). It exhibits dramatic consequences on SMA. These patients who were previously immobilized and succumbed to death acquired normal development by nusinersen therapy. They can walk and even run independently. Their life expectancy is considerably prolonged. It was licensed and approved by the FDA in 2016 (15). Vaccine for Alzheimer’s Disease Alzheimer’s disease (AD) is a devastating dementing disorder characterized by age-related Aβ deposition, neurofibrillary tangles, and synapse and neuronal loss. Late onset AD is the most common form and becomes symptomatic in later life. However, pathogenic protein Aβ is known to commence accumulating as earlier as 20 years at least. A treatment that could be used at this phase has been expected to prevent or slow down the inevitable fate of the patients. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. Therefore, there is an urgent need to develop a disease-modifying therapy that could be given 20 years prior to symptom onset. A growing body of evidence shows that immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Several phase 1 trials applying AAV vectors encoding anti-Aβ monoclonal antibodies caused a significant decrease in Aβ levels in the brain of mice models that showed great promise for their use for the prevention and treatment of AD (16). Parkinson’s Disease Parkinson’s disease (PD) is a neurodegenerative disorder that can be treated symptomatically but cannot be cured. Loss of the substantia nigra cells that produce dopamine is the primary cause. There are several trials targeting the gene coding aromatic l-amino acid decarboxylase-a key dopamine biosynthesis enzyme. Virus vector delivery of this enzyme into the bilateral putamen reported regression of symptoms in patients with moderate and advanced PD and provides stable and persistent transgene expression for >4 years (17).

Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is a disabling, progressive X-linked neuromuscular disorder for which there is no cure. It is caused by a lack of functional dystrophin protein resulting from mutations in the 2.2 Mb DMD gene. Several promising gene therapies are currently under investigation (12). One of these drugs, eteplirsen, an antisense oligonucleotide, received accelerated approval by the Food and Drug Administration (FDA) on September 19, 2016. Eteplirsen is specifically indicated for patients who have a confirmed mutation of the dystrophin gene due to exon 51 skipping, which affects approximately 13% of the population with DMD. The accelerated approval of eteplirsen is based on the consequence of dystrophin increase in the skeletal muscle observed in some treated patients although the clinical benefit of eteplirsen has not been established (13).

Table 3 outlines the gene therapy trials for these and additional neurological disorders (3, 8, 18).

Nusinersen for Spinal Muscular Atrophy Nusinersen is one of the great success stories of the biotechnology era. Previously, spinal muscular atrophy (SMA) was a disabling and progressively fatal disease of the spinal motor neurons. Nusinersen-an antisense oligonucleotide drug that modi-

Peer-review: Externally peer-reviewed.

CONCLUSION Neurological diseases had been conventionally admitted as incurable. Accelerating new inventions in gene- and biotechnologies have been changing this pessimistic paradigm for three decades. New disease biomarkers are being detected continuously that allow to diagnose neurodegenerative diseases in the prodromal phase that could be >20 years. A great deal of trials is in progress to restore this phase to prevent these hopeless diseases. Recently licensed therapies for congenital neuromuscular diseases promote these ambitious expectations to come true in the very near future.

Conflict of Interest: The author has no conflicts of interest to declare. Financial Disclosure: The author declared that this study has received no financial support.

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